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Bispecific antibodies for cancer therapy: The light at the end of the tunnel?
Open accessAbstract
With 23 approvals in the US and other countries and four approvals outside US, antibodies are now widely recognized as therapeutic molecules. The therapeutic and commercial successes met by rituximab, trastuzumab, cetuximab and other mAbs have inspired antibody engineers to improve the efficacy of these molecules. Consequently, a new wave of antibodies with engineered Fc leading to much higher effector functions such as antibody-dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity is being evaluated in the clinic, and several approvals are expected soon. In addition, research on a different class of antibody therapeutics, bispecific antibodies, has recently led to outstanding clinical results, and the first approval of the bispecific antibody catumaxomab, a T cell retargeting agent that was approved in the European Union in April 2009. This review describes the most recent advances and clinical study results in the field of bispecific antibodies, a new class of molecules that might outshine conventional mAbs as cancer immunotherapeutics in a near future.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
This review argues that after years of disappointing first-generation bispecific antibodies, engineered formats—especially triomabs and BiTEs—finally produced encouraging clinical results in cancer therapy. It highlights catumaxomab’s 2009 European approval for malignant ascites and blinatumomab’s potent T-cell–redirected activity in lymphoma and B-ALL.
Key findings
- First-generation bispecific antibodies (chemical cross-linking or quadromas) showed biological effects but no consistent antitumor activity; HAMA responses limited repeated dosing. HRS-3/A9 produced 1 complete remission and 1 partial remission in 15 patients in one Phase 1 study, then 1 CR and 3 PR in a second trial, but low yield (2.8 g bsAb from 44 g IgG) and high immunogenicity precluded further studies.
- Catumaxomab, an EpCAM x CD3 triomab, was approved by the European Commission in April 2009 for malignant ascites in EpCAM-positive carcinomas. In a Phase 2/3 pivotal study of 258 patients, catumaxomab gave a four-fold increase in puncture-free survival versus paracentesis alone; in a Phase 1/2 study, 22/23 patients did not require paracentesis between the last infusion and day 37, with up to 5-log reduction of EpCAM-positive malignant cells in ascites.
- Blinatumomab, a CD19 x CD3 BiTE, led to elimination of target cells in blood at doses as low as 5 μg/m²/day in relapsed NHL; all seven patients treated at 60 μg experienced tumor regression. In a Phase 2 B-ALL trial, 13/16 evaluable patients (81%) became MRD negative, with ongoing responses up to 47 weeks.
- DNL-based tri-Fabs showed high pretargeting performance: TF2 achieved tumor/blood ratios from 13 at 0.5 h to 395 at 24 h and tumor uptake of 30% ID/g; TF4 improved tumor-to-blood ratio 1,600-fold over a one-step anti-CD20 approach; TF10 gave tumor/blood ratios of 1,000:1 at 3 h versus 5:1 at 24 h for parental anti-MUC-1 IgG.
Methods
- Narrative review of bispecific antibody formats for cancer therapy, focusing on triomabs and BiTEs, with discussion of first-generation bsAbs, recombinant formats, BiTEs, and DNL antibodies.
- Synthesizes preclinical studies and clinical trials (Phase 1, 1/2, 2, and 2/3) reported in the literature up to 2009, including a table of recent clinical trials.
- No systematic search strategy, meta-analysis, or quantitative pooling is described.
Limitations
- The paper states that future randomized trials are needed to determine whether low amounts of bsAb achieve therapeutic effect; for catumaxomab IV Phase 1, survival analysis was not the primary endpoint.
- The paper notes that many bsAb trials were early-phase and small, and that some promising molecules had low production yields or high immunogenicity.
- Evident from the text: this is a narrative review without systematic search or meta-analysis, so format selection and cited evidence may be selective; the 2009 publication date means later clinical developments are not covered.
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Claims the paper makes
71 Not checked yet · 22 No basis given · 17 Own interpretation · 4 Own result · 1 Partly supported · accuracy not yet measured
In the paper
“Despite some obvious biological effects, none of these approaches led to a significant impact in the clinical course of disease. 8”
What the sources say
- Not checked yetcites [8] source
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“These results might be explained by preclinical data for MDX-210 indicating that measurable tumor-cell lysis required high bsAb concentrations (0.1-1 mg.mL -1 ) and effector-to-target cell ratios of at least 40:1, even when human neutrophils that had been prestimulated with IFNγ and G-CSF were used. 13”
What the sources say
- Not checked yetcites [13] source
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In the paper
“Bispecific antibodies directed against a tumor marker and CD3 have the potential to redirect and activate any circulating T cells against tumors.”
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In the paper
“Surprisingly, treatment with bsAbs of the most basic format, i.e., chemical cross-linking of full size monoclonal antibodies, yielded some success in clinical studies.”
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In the paper
“In animal studies, 100% of mice administered an injection of 4 μg of triomabs survived after intraperitoneal (IP) injection of a lethal dose of EpCAM + melanoma cells. 25”
What the sources say
- Not checked yetcites [25] source
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None of the sources cited for this claim have been checked yet.
In the paper
“The potential of using bispecific antibodies to retarget effector cells toward tumor cells was demonstrated in the 1980s 3,6,7”
What the sources say
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In the paper
“However, the low production yield (2.8 g of bsAb obtained from 44 g of IgG) and the high immunogenicity of this bsAb precluded further clinical studies.”
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In the paper
“many mAb shortcomings could be overcome by creating bispecific antibodies (bsAbs) capable of simultaneous binding to two different targets.”
What the sources say
- Not checked yetcites [3] source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“The construct was the first instance of bsAb treatment leading to a complete remission.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“A Phase 1/2 clinical trial using Her2Bi (OKT3 x trastuzumab)-armed activated T cells for the treatment of breast cancer and prostate cancer has resulted in partial responses persisting for two months following completion.”
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In the paper
“However, in March 2006, TGN1412, a monospecific 'superagonistic' CD28 antibody induced systemic T-cell activation and severe cytokine release syndrome when injected into six healthy volunteers, 42”
What the sources say
- Not checked yetcites [42] source
plaindirectn = 6- Asserted: passes — The authors put it forward as true.
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In the paper
“In a pilot study, Bi20 was administered to six patients with recurrent B cell malignancies, CLL or highly malignant lymphoma after allo-stem cell transplantation.All alemtuzumab-and rituximab-refractory patients showed a prompt but transient clinical and hematological response, highlighting the high therapeutic potential of this triomab.”
What the sources say
- Not checked yetcites [32] source
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Patients receiving catumaxomab had a four-fold increase in puncture-free survival compared to those receiving paracentesis therapy only.”
plaindirectn = 258- Asserted: passes — The authors put it forward as true.
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In the paper
“One atypical molecule was rM28, a bispecific tandem molecule targeting the co-stimulatory molecule CD28 expressed on T cells and NG2, a melanoma-associated proteoglycan.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In 1995, Kufer and collaborators produced such a tandem scFv targeting EpCAM (epithelial 17-1A antigen) and human CD3 in CHO cells.”
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In the paper
“This effective mode of action was recently extended to the cytolysis of lymphoma cells using an anti-CD28 x CD20 bispecific tandem scFv endowed with the same supra-agonistic properties. 41”
What the sources say
- Not checked yetcites [41] source
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In the paper
“However, it should be noted that a fundamental difference exists between TGN1412 and bispecific molecules such as rM28.”
plainn = 6- Asserted: passes — The authors put it forward as true.
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In the paper
“In an early clinical trial of patients with malignant ascites due to peritoneal carcinomatosis, administration of total doses of ertumaxomab as low as 40-140 μg lead to a complete elimination of tumor cells in ascites, and disappearance of ascites accumulation in all patients. 29”
What the sources say
- Not checked yetcites [29] source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“a promising anti-EGFR x CD3 diabody able to cure xenografted mice in combination with lymphokine activated killer cells, 38”
What the sources say
- Not checked yetcites [38] source
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In the paper
“In vitro, Bi20 was shown to mediate an efficient and specific lysis of B cell lines and B cells with low CD20 expression levels that were derived from chronic lymphocytic leukemia (CLL) patients. 31”
What the sources say
- Not checked yetcites [31] source
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In the paper
“Tumor cell monitoring revealed a reduction of EpCAM-positive malignant cells in ascites by up to 5 logs. 26”
What the sources say
- Not checked yetcites [26] source
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In the paper
“Numerous studies have demonstrated the potency of these formats in preclinical studies. 36”
What the sources say
- Not checked yetcites [36] Muller D, 2007, Curr Opin Mol Ther
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In the paper
“This new kind of bsAb proved to be highly cytotoxic at nanomolar concentrations against various cell lines, using unstimulated human PBMCs in the absence of co-signaling. 44”
What the sources say
- Not checked yetcites [44] source
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In the paper
“Indeed, unlike the activity of TGN1412, supra-agonistic CD28 stimulation by rM28 was shown to be strictly target-cell restricted over a wide concentration range, i.e., not induced if NG2-expressing target cells are absent. 43”
What the sources say
- Not checked yetcites [43] source
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In the paper
“It is also interesting to note that the high immunogenicity of this rat/mouse hybrid molecule did not constitute a major issue.”
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In the paper
“This is probably due to the extremely small amounts administered to the patients (around 100 μg”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“By early 2009, the results of a large international Phase 2/3 pivotal study involving 258 patients demonstrated a statistically significant improvement of the primary endpoint, puncture-free survival.”
boosteddirectn = 258- Asserted: passes — The authors put it forward as true.
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In the paper
“and the efficient treatment of xenografted mice bearing prostate cancer cell induced tumors using an anti-PSMA x CD3 diabody and peripheral blood lymphocytes. 39”
What the sources say
- Not checked yetcites [39] source
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In the paper
“In a Phase 1/2 clinical trial, patients in ovarian cancer patients with malignant ascites were treated with IP administration of triomab (4 to 5 doses of 5 to 200 μg); 22/23 patients did not require paracentesis between the last infusion and the end of study at day 37.”
What the sources say
- Not checked yetcites [26] source
plainn = 23- Asserted: passes — The authors put it forward as true.
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In the paper
“This, in principle, should avoid side effects such as those observed after TGN1412 administration.”
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In the paper
“All seven patients treated at a dose level of 60 μg experienced a tumor regression. 54”
What the sources say
- Not checked yetcites [54] source
plaindirectn = 7- Asserted: passes — The authors put it forward as true.
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In the paper
“The most impressive property of this class of molecules, beside the absence of requirement for any kind of pre or co stimulation of effector T cells, is the low concentration required to achieve anti-tumor activity.”
What the sources say
- Not checked yetcites [46] source
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In the paper
“BiTEs have been demonstrated to induce immunological cytolytic synapses identical to synapses induced by regular T cell stimuli, 49 even in the absence of MHC class I molecules, as shown by the lysis of EpCAM-expressing K562 cells or transfected rodent cells expressing the target antigen by human effector cells.”
What the sources say
- Not checked yetcites [49] source
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In the paper
“It relies on the spontaneous association of a dimer of the 45 amino acids peptide DDD2, derived from the regulatory subunit of human cAMP-dependent protein kinase (PKA) with the 21 residues peptide AD2, derived from the anchoring domains (AD) of human A kinase anchor proteins (AKAPs).”
What the sources say
- Not checked yetcites [61] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The small size (60 kDa) of BiTEs, which ensures close proximity of T cells and target cell membranes, might therefore be responsible for their high efficiency by leading to the active displacement of negative regulatory proteins from the forming synapse, as demonstrated in the case of CD45. 47”
What the sources say
- Not checked yetcites [47] source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This suggests that BiTEs mediate serial killing of many target cells, and this was actually demonstrated using video assisted microscopy. 16”
What the sources say
- Not checked yetcites [16] source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Preclinical data from studies with muS110, a BiTE surrogate targeting murine EpCAM and murine CD3 demonstrated that EpCAM-specific BiTE antibodies can effectively discriminate between target antigen expressed on tumor and normal epithelial tissue. 57”
What the sources say
- Not checked yetcites [57] source
boosteddirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The first results from an ongoing Phase 2 trial in patients with B-ALL indicate that T cells engaged by blinatumomab are able to locate and eradicate rare disseminated tumor cells in the bone marrow that can only be detected by quantitative PCR assays detecting tumor cell-specific genomic aberrations.”
hedgeddirectn = 16- Asserted: passes — The authors put it forward as true.
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In the paper
“MT110 was also active against human ovarian metastatic tissues grafted in immunodeficient mice in the absence of human peripheral mononuclear cells.”
What the sources say
- Not checked yetcites [56] source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Thus, the combination of bsAb-enabled pretargeting approaches and this radionuclide might have a high therapeutic potential.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: The emitted beta radiation of 177Lu with a maximum energy of 498 keV is effective in destroying small tumors and metastasis while sparing normal tissue.
- Rests on an assumption: 177Lu gamma rays are of low energy (113 and 208 keV) and abundance (7 and 11%), which simplifies radiation protection and patient-handling issues.
In the paper
“In preclinical trials, Dreier et al. demonstrated that submicrogram amounts of this molecule were sufficient to prevent tumor growth in a mouse model. 52”
What the sources say
- Not checked yetcites [52] source
boosteddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“by a mere interaction between CD3 and a target antigen via a BiTE molecule, in the absence of MHC class I/TCR interaction, has the potential to overcome many tumor cell escape mechanisms such as MHC class I, proteasome and intracellular peptide transporter (TAP1 and 2) downregulation.”
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In the paper
“Indeed, most tumor cell lines can be lysed in the presence of 0.2 to 2 pM of BiTEs for half maximal target cell lysis.”
What the sources say
- Not checked yetcites [46] source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that a low two digit number of BiTEs bound between T and target cells is sufficient to induce lysis.”
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“A study in NOD/SCID mice demonstrated that as little as 100 ng of MT110 can prevent tumor outgrowth after an injection of a 1:1 ratio of human colon carcinoma cells mixed with unstimulated human peripheral mononuclear cells.”
What the sources say
- Not checked yetcites [55] source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The small size (60 kDa) of BiTEs, which ensures close proximity of T cells and target cell membranes, might therefore be responsible for their high efficiency by leading to the active displacement of negative regulatory proteins from the forming synapse, as demonstrated in the case of CD45. 47”
What the sources say
- Not checked yetcites [47] source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“In 2008, the first result of a Phase 1 clinical study indicated that doses as low as 5 μg per square meter per day in relapsed NHL patients led to an elimination of target cells in blood.”
What the sources say
- Not checked yetcites [54] source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results were in marked contrast with the majority of published studies based on anti-CD3 bispecific constructs.”
boosted- Asserted: passes — The authors put it forward as true.
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In the paper
“MT111/MEDI-565 targets the carcinoembryonic antigen (CEA, also called CEACAM5), a widely expressed tumor antigen highly expressed in colorectal cancer, and also in a substantial proportion of carcinomas of the lung, pancreas, stomach, ovary, uterus, breast and a subset of melanomas. 58”
What the sources say
- Not checked yetcites [58] source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In some cases, up to 18 fM was shown to be enough to induce in vitro cell lysis”
What the sources say
- Not checked yetcites [47] source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
In the paper
“In vitro characterizations of MT110 have recapitulated the results obtained with MT103 on tumor cell lines, thereby demonstrating the generality of the BiTE format. 55”
What the sources say
- Not checked yetcites [55] source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Moreover, BiTEs are capable of inducing efficient lysis at effector to target ratios (E:T) as low as 1:10.”
What the sources say
- Not checked yetcites [16] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Studies performed in xenografted nude mice that compared TF4 as a pretargeting agent of an 111 In-HSG-peptide with a one step approach using the parental anti-CD20 mAb (hA20) directly labeled with 90 Y demonstrated an impressive 1,600-fold improvement of the tumor-to-blood ratio, as well as a 1.6-fold improvement of tumor uptake. 63”
What the sources say
- Not checked yetcites [63] source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This soluble CEA (sCEA) might therefore interfere with antibody based therapies.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: CEA can be shed by phospholipases from the cell surface through cleavage of its glycosylphosphatidylinositol-linkage, causing release into the circulation.
In the paper
“Lutterbuese et al. compared the activity of several anti-CEA x anti-CD3 BiTE in the absence or presence of sCEA, and found that the cytotoxic activity of some of these molecules was not competitively inhibited by sCEA at concentrations that exceeded levels found in the serum of most cancer patients. 59”
What the sources say
- Not checked yetcites [59] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: CEA can be shed by phospholipases from the cell surface through cleavage of its glycosylphosphatidylinositol-linkage, causing release into the circulation.
In the paper
“Both BiTEs have already been investigated in studies with macaque monkeys that have validating these new molecules, both in terms of efficacy and safety. 60”
What the sources say
- Not checked yetcites [60] Kischel R, 2008, Proc Am Assoc Cancer Res
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 50
- Probably not a substantial claim. 17
- The quote only partly states this claim. 1
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Biological effects were seen in some clinical trials of bsAbs MDX-210 (targeting Her2 and CD64), MDX-H210 (humanized version of MDX-210) and MDX-447 (targeting EGFR and CD64), but none of these treatments led to consistent antitumor activity. [9][10]0][11][12]”
What the sources say
- Not checked yetcites [9] source
- Partly supportedcites [10] sourceExperimental — accuracy not yet measured
The Abstract reports biological effects with MDX-H210 plus G-CSF, and the Results > Response section reports no objective responses in that single-dose trial (page numbers unavailable). The paper does not establish the claimed biological effects and lack of consistent antitumor activity across trials of MDX-210 and MDX-447; its Discussion mentions MDX-447 only in relation to toxicity. (LLM, conf=0.87)
- Partly supportedcites [11] sourceExperimental — accuracy not yet measured
The Phase II and MDX-447 Clinical Experience sections report biological effects and limited tumor responses, including two responses among ten assessable patients given MDX-210 alone and stable disease in nine of 36 patients evaluated for MDX-447. The Conclusions describe the antitumor effects of MDX-H210 and MDX-447 as promising, but the paper does not establish the categorical claim that none of the three treatments produced consistent antitumor activity. Page numbers are unavailable in our copy. (LLM, conf=0.79)
- Partly supportedcites [12] sourceExperimental — accuracy not yet measured
The Discussion (page not provided) reports increased MDX-447 binding to neutrophils and no objective responses in either MDX-447 treatment group. It discusses MDX-H210 trials only in relation to tolerability, not biological effects or antitumor activity, and the searched passages do not establish those outcomes for MDX-210. Thus this source supports the MDX-447 portion, but not the claim about all three treatments. (LLM, conf=0.87)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Human anti-mouse antibody (HAMA) responses were seen in most treated patients, which severely decreased the efficacy of the murine molecules and excluded the possibility of multiple administrations.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Such molecules would be capable of retargeting a large variety of payloads to cancer cells.”
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“This approach has the advantage of avoiding a direct systemic injection of bsAb in the patient, thereby significantly minimizing toxicity associated with free murine Fc bearing molecules. 19”
What the sources say
- Not checked yetcites [19] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In short, this Fc adds two crucial functions to regular anti-CD3 x target bsAbs: additive tumor killing capabilities through the efficient recruitment of macrophages and NK cells and, most importantly, efficient co-stimulation of T cells through direct contact with accessory cells such as macrophages of efficacy”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Moreover, EpCAM is very often on cancer stem cells, a very attractive feature for a tumor marker. 24”
What the sources say
- Not checked yetcites [24] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Two Phase 1 clinical studies performed with this molecule led to one complete remission (CR) and one partial remission (PR) in a group of 15 treated patients; 14 this was followed by one CR and three PR in a second clinical trial. 15”
What the sources say
- Not checked yetcites [14] Hartmann F, 1997, Blood source
- Not checked yetcites [15] Hartmann F, 2001, Clin Cancer Res
plaindirectn = 15- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“EpCAM is also expressed in normal cells, but is predominantly located in intercellular spaces where epithelial cells form very tight junctions.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The first studies of bsAbs highlighted two major limitations of the first generation molecules, including the difficulty of producing large, homogeneous batches, and the lack”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The second specificity of these bsAbs was directed against FcγRI (CD64), which is notably expressed on monocytes and macrophages and upregulated upon activation on neutrophils.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“They are abundant, efficiently proliferate upon activation, capable of killing multiple times 16 and efficiently infiltrate tumors, but do not express Fcγ receptors.”
What the sources say
- Not checked yetcites [16] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“A series of clinical trials were also performed with chemically linked bispecific (Fab')2 molecules targeting the breast and ovarian cancer tumor antigens HER2 or EGFR, [9][10][11][12] which are overexpressed in many epithelial tumors such as colorectal, head and neck, bladder, renal, non-small cell lung carcinoma.”
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“EpCAM (CD326) is expressed on essentially all human adenocarcinoma, certain squamous cell carcinoma, retinoblastoma and hepatocellular carcinoma.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Surprisingly, the resulting hybrid rat/mouse Fc portion efficiently interacted with activating human Fc receptors (FcγRI and FcγRIII), but not inhibitory ones (FcγRIIB), thereby reaching the goal that other groups had hoped to achieve using human Fc engineering. 22,23”
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The first anti-CD3 bsAbs were thus administered in combination with anti-CD28 antibodies, but the combination yielded mixed results. 18”
What the sources say
- Not checked yetcites [18] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Interestingly, it was shown that bsAb-retargeted PACTs can divide and secrete cytokines upon restimulation with target cells, while retaining their specificity and cytotoxicity for more than two weeks, which might be an important feature for therapeutic settings. 20”
What the sources say
- Not checked yetcites [20] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Catumaxomab, which targets the tumor antigen EpCAM, was the first triomab produced.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Without the secondary signal given by the interaction between CD28 and one of its ligands (e.g., B7), T cells are not fully activated, and might even become anergic. 17”
What the sources say
- Not checked yetcites [17] source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The investigators used this approach to create an anti-CD3 x anti-EpCAM bsAb, and demonstrated that this antibody was capable of binding to target cells and human T cells, but was also capable of activating dendritic cells (DC), inducing NK-dependent ADCC and stimulating tumor cell phagocytosis by macrophages. 22,23”
What the sources say
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“limitations in their modes of action, including redundancy of molecular pathways leading to cancer cell survival, effects of the microenvironment, suboptimal interaction with effector cells due to alternative Fc glycosylation or Fc receptor polymorphism, activation of inhibitory receptors, and competition with circulating IgG. 2”
What the sources say
- Not checked yetcites [2] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“By using an original subclass combination (mouse IgG2a and rat IgG2b), they demonstrated a preferential speciesrestricted heavy/light chain pairing, in contrast to the random pairing in conventional mouse/mouse or rat/rat quadromas, as well as use of sequential pH elution on protein A to easily separate the desired bsAb from the parental mAb.”
What the sources say
- Not checked yetcites [21] Lindhofer H, 1995, J Immunol source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Although difficult to produce in E. coli, this 60 kDa molecule is well-expressed by mammalian cells.”
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Below the maximum tolerated dose (200 μg), side effects, including fever, nausea and vomiting, were predictable, limited, manageable and mostly fully transient. 27”
What the sources say
- Not checked yetcites [27] Parsons S, 2009, J Clin Oncol
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In comparison, rituximab demonstrated a significantly lower B cell eradication rate. 31”
What the sources say
- Not checked yetcites [31] source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
In the paper
“This effect was dependent on the presence of the hybrid Fc, and involved a humoral response directed against the non-transfected (EPCAM -) tumor cells.”
What the sources say
- Not checked yetcites [25] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“This triomab possesses the same hybrid Fc portion as catumaxomab, and displays the same efficiency in vitro. 29”
What the sources say
- Not checked yetcites [29] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“All mice rechallenged on day 144 after the primary challenge were still able to reject the tumor, indicating the high efficacy and long duration of the antitumor response.”
What the sources say
- Not checked yetcites [25] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Surprisingly, no bispecific diabodies have been tested so far in clinical trials.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In the nineties, advances in antibody engineering provided innovative solutions antibody design problems, allowing production of small antibody fragments recapitulating the entire binding activity of the parent molecule (Fig. 1).”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“These molecules can be expressed at high yields in bacteria and have been shown by crystallography experiments to adopt several conformations. 35”
What the sources say
- Not checked yetcites [35] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Moderate anti mouse and anti rat responses were seen in the majority of the patients but they do not seem to affect the efficiency of the treatment. 26”
What the sources say
- Not checked yetcites [26] source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Tandem scFvs (TaFv) are two scFv fragments linked by an extra peptide linker that is expected to confer good flexibility to each fragment.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Expressed on all stages of B cell development from pre-B cells through memory cells, but not on either pro-B cells or plasma cells, CD20 represents an attractive target for the treatment of B cell malignancies.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
In the paper
“f note, two other triomabs, targeting melanoma-associated proteoglycans or melanoma-associated gangliosides (GD2 and GD3), 33 are in preclinical studies as potential treatments for malignant melanoma.”
What the sources say
- Not checked yetcites [33] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“T cell activation and tumor cell killing occurred in an entirely autologous setting, i.e., without additional effector cells, in 5 of 8 samples.”
What the sources say
- Not checked yetcites [31] source
plaindirectn = 8- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This difference can probably be explained by the mode of action of these antibodies.Trastuzumab triggers NK-mediated ADCC, while ertumaxomab relies on T cell mediated killing and the interaction between T cells and accessory cells, as demonstrated by the release of proinflammatory cytokines such as IL-6, IFNγ and TNFα.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Exposure to ertumaxomab led to the efficient lysis of cells expressing very low amount of tumor antigen, whereas trastuzumab was completely ineffective even at high concentration. 30”
What the sources say
- Not checked yetcites [30] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“This molecule spontaneously forms stable dimers, and was shown to be capable of inducing T-cell activation and effective tumor-cell killing in vitro and in vivo without a signal through the TCR/CD3 complex, a so called”
What the sources say
- Not checked yetcites [40] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Ertumaxomab is triomab targeting HER2, a well-characterized breast tumor marker that is also targeted by trastuzumab (Herceptin).”
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“BiTEs, or bispecific T cell Engagers, are made by fusing an anti-CD3 scFv to an anti-TAA scFv via a short five residue peptide linker (GGGGS).”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“This molecule demonstrated outstanding in vitro properties, including efficient cytotoxicity induced by extremely low concentrations of bsAb (10-50 pg.mL -1 , i.e., subpicomolar), at low effector:target ratio (2:1), and in only four hours, without the need for pre-stimulation of T cells or, most surprisingly, the need of co-signaling (e.g., through CD28).”
What the sources say
- Not checked yetcites [45] Loffler A, 2000, Blood source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Bi20 triomab utilizes the same hybrid Fc portion as catumaxomab and ertumaxomab, and targets CD20.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It should be highlighted that cumulative doses of several milligrams were sufficient to lead to the notable response in patients, whereas conventional antibody treatments, such as rituximab, consume gram amounts per treatment cycle.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Exceptionally high tumor blood ratios were observed, ranging from 13 at 0.5 h to 395 at 24 h, with high tumor uptake of 30% ID/g, whereas the levels in blood and normal tissues, except kidney, were <1% ID/g at 1 h after injection.”
What the sources say
- Not checked yetcites [61] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Blinatumomab, a murine antihuman CD3 x anti-human CD19 was the first BiTE developed and is the most advanced BiTE in clinical trials.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“The absence of a need for co-signaling through CD28 for these BiTEs might also be explained by the observation that among all T cell subtypes, CD8 + effector memory cells CD45RO + (TEM) and CD8 + effector memory CD45RA + (TEMRA) contribute the most to BiTE activity, whereas naïve T cells do not contribute at all to the killing efficiency. 50”
What the sources say
- Not checked yetcites [50]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“MT110, an anti-human EpCAM x anti-human CD3 TaFv, was the second BiTE tested in clinical trial and the”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“This result is remarkable since MRD positive ALL patients have very limited treatment options, and around 60% of patients die within 2 years, with a median time to hematological relapse of only 4.1 months.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“Since MT110 does not activate murine T cells, this result suggests that tumor resident human T cells, being tolerized or anergized, could be reactivated, and were present in sufficient number to eliminate the xenograft. 56”
What the sources say
- Not checked yetcites [56] source
hedgeddirectSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: MT110 does not activate murine T cells.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thirteen out of 16 evaluable patients (81%) became minimum residual disease (MRD) negative, with ongoing responses lasting for up to 47 weeks on May the 25 th 2009 (data presented in Recombinant Antibodies meeting, June 2009, Cologne).”
plainn = 16- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Despite this extreme efficiency, the killing remains strictly target-cell dependent, and T cells cannot be activated in the absence of target cells, even at concentrations exceeding EC 50 values by several thousand fold. 48”
What the sources say
- Not checked yetcites [48] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Interestingly, this trial was associated with significantly reduced toxicity compared to NHL patients at the same dose level, suggesting that toxicity might be correlated to the number of target cells present in patients, rather than to the BiTE molecule itself.”
hedgedcorrelationaln = 16- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Upon association, two disulfide bonds are created, resulting in a covalent complex that is stable for more than a week at 37°C in human serum.”
What the sources say
- Not checked yetcites [61] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The first described bsAb built using the DNL method was a molecule of 157 kDa, devoid of Fc fragment, comprising two Fab fragments derived from humanized anti-human CEA mAb hMN-14 and one Fab fragment from humanized mAb h679 that is able to strongly bind the hapten histamine-succinyl-glycine (HSG).”
What the sources say
- Not checked yetcites [61] source
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“This can be used to efficiently create any kind of bsAb, but was so far used to create bispecific molecules dedicated to radioimmunotherapy.”
What the sources say
- Not checked yetcites [61] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Later, studies performed in chimpanzees showed that repeated 2 h treatments with doses as low as 0.1 μg.kg -1 were welltolerated, and led to cumulative depletion of peripheral B cells due to fully reversible T cell activation. 53”
What the sources say
- Not checked yetcites [53] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Because of its small size (60 kDa), blinatumomab is characterized by a short serum half life of several hours, and so continuous intravenous infusion by portable mini-pumps is required.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“TF4 is a second bsAb built using the DNL method, directed against CD20 for the treatment of NHL.”
What the sources say
- Not checked yetcites [63] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“PAM-4, the parental anti-MUC-1 antibody has been shown to bind a MUC1 epitope that is not detected in normal pancreas but is expressed in 87% of invasive pancreatic adenocarcinomas, including early stage 1 disease. 64”
What the sources say
- Not checked yetcites [64] source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
Cytotoxic T cells are the most potent killer cells of the immune system.
“Cytotoxic T cells are considered the most potent killer cells of the immune system.”
The paper relies on this without support.
EpCAM is sequestered on epithelia and thus much less accessible to antibodies compared to EpCAM in cancer tissue, where it is homogeneously distributed on the cancer cell surface.
“It is thought that EpCAM is sequestered on epithelia, and thus much less accessible to antibodies compared to EpCAM in cancer tissue, where it is homogeneously distributed on the cancer cell surface.”
The paper relies on this without support.
Memory T cells do not require CD28 costimulation for expansion during secondary responses.
“It is believed that memory T cells do not require CD28 costimulation for expansion during secondary responses, which could explain the efficiency of BiTEs.”
The paper relies on this without support.
None of the approved monoclonal antibodies are able to cure cancer as single agents.
“Unfortunately, none of them are able to cure cancer as single agents.”
The paper relies on this without support.
BiTE molecules targeting EpCAM expressed on solid tumors of epithelial origin that do not express B7 show similar efficacy.
“However, BiTE molecules targeting EpCAM expressed on a variety of solid tumor of epithelial origin that do not express B7 show similar efficacy.”
The paper relies on this without support.
CEA can be shed by phospholipases from the cell surface through cleavage of its glycosylphosphatidylinositol-linkage, causing release into the circulation.
“However, CEA can be shed by phospholipases from the cell surface through cleavage of its glycosylphosphatidylinositol-linkage, which causes the protein to be released in the circulation.”
The paper relies on this without support.
The emitted beta radiation of 177Lu with a maximum energy of 498 keV is effective in destroying small tumors and metastasis while sparing normal tissue.
“Furthermore, the emitted β radiation with a maximum energy of 498 keV is effective in destroying small tumors and metastasis while sparing normal tissue”
The paper relies on this without support.
177Lu gamma rays are of low energy (113 and 208 keV) and abundance (7 and 11%), which simplifies radiation protection and patient-handling issues.
“and its γ-rays are of low energy (113 and 208 keV) and abundance (7 and 11%), which simplifies radiation protection and patient-handling issues.”
The paper relies on this without support.
MT110 does not activate murine T cells.
“Since MT110 does not activate murine T cells”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“One of the most active areas of bsAbs application is in the field of cancer immunotherapy.85, 86, 87”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [85]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ BiTEs: Bispecific T Cell Engagers
“In 1995, Kufer and collaborators produced such a tandem scFv targeting EpCAM (epithelial 17-1A antigen) and human CD3 in CHO cells.This new kind of bsAb proved to be highly cytotoxic at nanomolar concentrations against various cell lines, using unstimulated human PBMCs in the absence of co-signaling. 44”
§ References
“44. Fury MG, Lipton A, Smith KM, Winston CB, Pfister DG. A phase-I trial of the epidermal growth fac- tor receptor directed bispecific antibody MDX-447 without and with recombinant human granulocyte- colony stimulating factor in patients with advanced solid tumors. Cancer Immunol Immunother 2008; 57:155-63.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ The New Generation: Recombinant bsAbs
“In 2008, the first result of a Phase 1 clinical study indicated that doses as low as 5 μg per square meter per day in relapsed NHL patients led to an elimination of target cells in blood.All seven patients treated at a dose level of 60 μg experienced a tumor regression. 54”
§ References
“54. Zeidler R, Mysliwietz J, Csanady M, Walz A, Ziegler I, Schmitt B, et al. The Fc-region of a new class of intact bispecific antibody mediates activation of accessory cells and NK cells and induces direct phagocytosis of tumour cells. Br J Cancer 2000; 83:261-6.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ TriomAbs
“In 1995, Lindhofer and collaborators published a paper describing a major improvement of the classical quadroma approach to produce bsAbs. 21”
§ References
“21. Schlereth B, Quadt C, Dreier T, Kufer P, Lorenczewski G, Prang N, et al. T-cell activation and B-cell deple- tion in chimpanzees treated with a bispecific anti- CD19/anti-CD3 single-chain antibody construct. Cancer Immunol Immunother 2006; 55:503-14.”
Citations
Cites
Continuous cultures of fused cells secreting antibody of predefined specificity
Köhler, G., & Milstein, C. (1975) · Nature · doi:10.1038/256495a0 · Cited by 17,200
Naturally occurring antibodies devoid of light chains
Hamers-Casterman, C., Atarhouch, T., Muyldermans, S., Robinson, G., Hammers, C., Songa, E. B., Bendahman, N., & Hammers, R. (1993) · Nature · doi:10.1038/363446a0 · Cited by 3,241
FcRn: the neonatal Fc receptor comes of age
Roopenian, D. C., & Akilesh, S. (2007) · Nature Reviews Immunology · doi:10.1038/nri2155 · Cited by 2,346
Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412
Suntharalingam, G., Perry, M. R., Ward, S., Brett, S. J., Castello-Cortes, A., Brunner, M. D., & Panoskaltsis, N. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa063842 · Cited by 2,164
Cartron, G., Dacheux, L., Salles, G. A., Solal‐Céligny, P., BARDOS, P., Colombat, P., & Watier, H. (2002) · Blood · doi:10.1182/blood.v99.3.754 · Cited by 1,954
Engineered antibody fragments and the rise of single domains
Holliger, P., & Hudson, P. J. (2005) · Nature Biotechnology · doi:10.1038/nbt1142 · Cited by 1,928
Therapeutic antibodies: successes, limitations and hopes for the future
Chames, P., Van Regenmortel, M., Weiss, E., & Baty, D. (2009) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2009.00190.x · Cited by 1,382
Self-citationTumor Regression in Cancer Patients by Very Low Doses of a T Cell–Engaging Antibody
Bargou, R., Leo, E., Zugmaier, G., Klinger, M., Goebeler, M., Knop, S., Noppeney, R., Viardot, A., Hess, G., Schuler, M., et al. (2008) · Science · doi:10.1126/science.1158545 · Cited by 1,078
Ward, E. S., Güssow, D., Griffiths, A. D., Jones, P., & Winter, G. P. (1989) · Nature · doi:10.1038/341544a0 · Cited by 1,010
"Diabodies": small bivalent and bispecific antibody fragments.
Holliger, P., Prospero, T. D., & Winter, G. P. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.14.6444 · Cited by 882
Research works printed but not linked: 6
- Chames P, 2009, Curr Opin Drug Discov Devel, 12, 276
- Hartmann F, 2001, Clin Cancer Res, 7, 1873
- Parsons S, 2009, J Clin Oncol, 27
- Muller D, 2007, Curr Opin Mol Ther, 9, 319
- Kischel R, 2008, Proc Am Assoc Cancer Res, 99, 2404
- McBride WJ, 2006, J Nucl Med, 47, 1678
Cited by
Sorted by citations
Nanobodies: natural single-domain antibodies
Muyldermans, S. (2013) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-063011-092449 · Cited by 2,304
Bispecific antibodies: a mechanistic review of the pipeline
Labrijn, A. F., Janmaat, M. L., Reichert, J. M., & Parren, P. W. H. I. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0028-1 · Cited by 1,303
Combination cancer immunotherapies tailored to the tumour microenvironment
Smyth, M. J., Ngiow, S. F., Ribas, A., & Teng, M. W. L. (2016) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2015.209 · Cited by 944
The making of bispecific antibodies
Brinkmann, U., & Kontermann, R. E. (2017) · mAbs · doi:10.1080/19420862.2016.1268307 · Cited by 961
Strategies and challenges for the next generation of therapeutic antibodies
Beck, A., Wurch, T., Bailly, C., & Corvaı̈a, N. (2010) · Nature reviews. Immunology · doi:10.1038/nri2747 · Cited by 868
Metadata
- Authors
- Chames, P., & Baty, D.
- Affiliations
- Inserm (FR)
- Venue
- mAbs
- Publisher
- Informa UK Limited
- Published
- 2009-11
- Volume
- 1
- Issue
- 6
- Pages
- 539-547
- ISSN
- 1942-0862 (ISSN-L)
- 1942-0870
- PMC
- PMC2791310
- OpenAlex
- W1848910860
- Semantic Scholar
- f85480341850bb514971c5c8b11769d3ec48fa5b
- Cited by
- 336
- References
- 105
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 11 · 2023: 11 · 2022: 18 · 2021: 12 · 2020: 16 · 2019: 18 · 2018: 22 · 2017: 25 · 2016: 18 · 2015: 30 · 2014: 32 · 2013: 46 · 2012: 24
- FWCI
- 3.12
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- mAbs (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › Toxin Mechanisms and Immunotoxins
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
- Keywords
- bispecific antibodies, cancer immunotherapy, antibody engineering, catumaxomab, T cell redirection, antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, monoclonal antibodies, clinical trials
- MeSH terms
- Animals, Antibody Specificity, Antineoplastic Agents, Humans, Immunotherapy, Neoplasms, Recombinant Proteins, Protein Engineering, Treatment Outcome, Antibodies, Bispecific
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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