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Cited by 336Monoclonal and Polyclonal Antibodies ResearchToxin Mechanisms and ImmunotoxinsRadiopharmaceutical Chemistry and Applications

Bispecific antibodies for cancer therapy: The light at the end of the tunnel?

Open access
Chames, Patrick, Baty, Daniel·2009·mAbs
DOI 10.4161/mabs.1.6.10015PMC PMC2791310
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Abstract

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.

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.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.4161/mabs.1.6.10015

Cites

105 of 105 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 83 cited sources checked · 0 supported · 0 flagged

  • Premisecitation
    § First Generation bsAbs: Chemically Cross-Linked Bispecific Antibodies

    Early bispecific antibody approaches using chemical cross-linking or hybrid hybridomas/quadromas did not lead to a significant impact in the clinical course of disease despite some biological effects.

    “Despite some obvious biological effects, none of these approaches led to a significant impact in the clinical course of disease. 8”
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    • cites [8] source

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  • Premisecitation
    § TriomAbs

    Preclinical data for MDX-210 indicated that measurable tumor-cell lysis required high bispecific antibody concentrations (0.1-1 mg.mL-1) and effector-to-target cell ratios of at least 40:1, even when human neutrophils prestimulated with IFNγ and G-CSF were used.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] source

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  • Interpretationreasoning
    § TriomAbs

    Bispecific antibodies directed against a tumor marker and CD3 have the potential to redirect and activate any circulating T cells against tumors.

    “Bispecific antibodies directed against a tumor marker and CD3 have the potential to redirect and activate any circulating T cells against tumors.”
    Quote in the paperSubstantial claim
  • Premisenone given
    § TriomAbs

    Treatment with bispecific antibodies of the most basic format, chemical cross-linking of full size monoclonal antibodies, yielded some success in clinical studies.

    “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.”
    Quote in the paperNot a substantial claim
  • Premisecitation
    § Catumaxomab (Removab ® )

    In animal studies, 100% of mice administered an injection of 4 μg of triomabs survived after intraperitoneal injection of a lethal dose of EpCAM+ melanoma cells.

    “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”
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  • May combine two claims. 50
  • Classified as probably not a substantial claim. 17
  • The quote only partly states this claim. 1

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    Premisenone given
    § TriomAbs

    Human anti-mouse antibody responses were seen in most treated patients, severely decreased the efficacy of murine molecules, and excluded the possibility of multiple administrations.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning
    § Introduction

    Bispecific antibodies are capable of retargeting a large variety of payloads to cancer cells.

    “Such molecules would be capable of retargeting a large variety of payloads to cancer cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation
    § Bispecific antibodies for cancer therapy

    The PACT approach avoids direct systemic injection of bispecific antibody in the patient, thereby significantly minimizing toxicity associated with free murine Fc bearing molecules.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
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  • May combine two claims.

    Interpretationreasoning
    § TriomAbs

    The hybrid Fc adds two crucial functions to regular anti-CD3 x target bispecific antibodies: additive tumor killing through efficient recruitment of macrophages and NK cells, and efficient co-stimulation of T cells through direct contact with accessory cells.

    “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”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Catumaxomab (Removab ® )

    EpCAM is very often on cancer stem cells, a very attractive feature for a tumor marker.

    “Moreover, EpCAM is very often on cancer stem cells, a very attractive feature for a tumor marker. 24”
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    • cites [24] source

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    Premisecitation
    § TriomAbs

    Two Phase 1 clinical studies of HRS-3/A9 led to one complete remission and one partial remission in 15 treated patients; a second trial led to one complete remission and three partial remissions.

    “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”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Hartmann F, 1997, Blood source

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    • cites [15] Hartmann F, 2001, Clin Cancer Res

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  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given
    § Catumaxomab (Removab ® )

    EpCAM is also expressed in normal cells, but is predominantly located in intercellular spaces where epithelial cells form very tight junctions.

    “EpCAM is also expressed in normal cells, but is predominantly located in intercellular spaces where epithelial cells form very tight junctions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning
    § First Generation bsAbs: Chemically Cross-Linked Bispecific Antibodies

    First generation bispecific antibodies had two major limitations: difficulty producing large homogeneous batches and lack of efficacy of murine antibody fragments.

    “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”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given
    § TriomAbs

    The second specificity of these bispecific antibodies was directed against FcγRI (CD64), which is expressed on monocytes and macrophages and upregulated upon activation on neutrophils.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § TriomAbs

    T cells are abundant, efficiently proliferate upon activation, are capable of killing multiple times, and efficiently infiltrate tumors, but do not express Fcγ receptors.

    “They are abundant, efficiently proliferate upon activation, capable of killing multiple times 16 and efficiently infiltrate tumors, but do not express Fcγ receptors.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] source

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  • May combine two claims.

    Premisecitation
    § TriomAbs

    Chemically linked bispecific (Fab')2 molecules targeting HER2 or EGFR were tested in clinical trials; these antigens are overexpressed in many epithelial tumors such as colorectal, head and neck, bladder, renal, and non-small cell lung carcinoma.

    “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.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [9] source

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  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given
    § Catumaxomab (Removab ® )

    EpCAM is expressed on essentially all human adenocarcinoma, certain squamous cell carcinoma, retinoblastoma and hepatocellular carcinoma.

    “EpCAM (CD326) is expressed on essentially all human adenocarcinoma, certain squamous cell carcinoma, retinoblastoma and hepatocellular carcinoma.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § TriomAbs

    The hybrid rat/mouse Fc portion efficiently interacted with activating human Fc receptors FcγRI and FcγRIII, but not with inhibitory FcγRIIB.

    “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”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] source

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    • cites [23] Zeidler R, 1999, J Immunol source

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  • May combine two claims.

    Premisecitation
    § TriomAbs

    Biological effects were seen in some clinical trials of MDX-210, MDX-H210 and MDX-447, but none of these treatments led to consistent antitumor activity.

    “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]”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [9] source

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  • May combine two claims.

    Premisecitation
    § TriomAbs

    The first anti-CD3 bispecific antibodies were administered in combination with anti-CD28 antibodies, but the combination yielded mixed results.

    “The first anti-CD3 bsAbs were thus administered in combination with anti-CD28 antibodies, but the combination yielded mixed results. 18”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] source

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  • May combine two claims.

    Premisecitation
    § Bispecific antibodies for cancer therapy

    Bispecific antibody-retargeted PACTs can divide and secrete cytokines upon restimulation with target cells, while retaining their specificity and cytotoxicity for more than two weeks.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given
    § Catumaxomab (Removab ® )

    Catumaxomab targets the tumor antigen EpCAM and was the first triomab produced.

    “Catumaxomab, which targets the tumor antigen EpCAM, was the first triomab produced.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § TriomAbs

    Without the secondary signal given by the interaction between CD28 and one of its ligands such as B7, T cells are not fully activated and might become anergic.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] source

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  • May combine two claims.

    Premisecitation
    § TriomAbs

    An anti-CD3 x anti-EpCAM bispecific antibody created with this approach was capable of binding target cells and human T cells, activating dendritic cells, inducing NK-dependent ADCC, and stimulating tumor cell phagocytosis by macrophages.

    “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”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] source

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    • cites [23] Zeidler R, 1999, J Immunol source

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  • May combine two claims.

    Premisecitation
    § Introduction

    Monoclonal antibody modes of action have major limitations, 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.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
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  • May combine two claims.

    Premisecitation
    § TriomAbs

    Using an original subclass combination of mouse IgG2a and rat IgG2b, Lindhofer and collaborators demonstrated preferential species-restricted heavy/light chain pairing, in contrast to random pairing in conventional quadromas, and sequential pH elution on protein A to separate the desired bispecific antibody from parental monoclonal antibody.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Lindhofer H, 1995, J Immunol source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given
    § Catumaxomab (Removab ® )

    Although difficult to produce in E. coli, the 60 kDa TaFv molecule is well-expressed by mammalian cells.

    “Although difficult to produce in E. coli, this 60 kDa molecule is well-expressed by mammalian cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Catumaxomab (Removab ® )

    Below the maximum tolerated dose (200 μg), side effects including fever, nausea and vomiting were predictable, limited, manageable and mostly fully transient.

    “Below the maximum tolerated dose (200 μg), side effects, including fever, nausea and vomiting, were predictable, limited, manageable and mostly fully transient. 27”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Parsons S, 2009, J Clin Oncol

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  • The quote only partly states this claim.

    Premisecitation
    § Catumaxomab (Removab ® )

    Rituximab demonstrated a significantly lower B cell eradication rate compared to Bi20.

    “In comparison, rituximab demonstrated a significantly lower B cell eradication rate. 31”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation
    § Catumaxomab (Removab ® )

    The antitumor effect was dependent on the presence of the hybrid Fc and involved a humoral response directed against non-transfected (EPCAM-) tumor cells.

    “This effect was dependent on the presence of the hybrid Fc, and involved a humoral response directed against the non-transfected (EPCAM -) tumor cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] source

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  • May combine two claims.

    Premisecitation
    § Ertumaxomab (Rexomun ® )

    Ertumaxomab possesses the same hybrid Fc portion as catumaxomab and displays the same efficiency in vitro.

    “This triomab possesses the same hybrid Fc portion as catumaxomab, and displays the same efficiency in vitro. 29”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] source

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  • May combine two claims.

    Premisecitation
    § Catumaxomab (Removab ® )

    All mice rechallenged on day 144 after the primary challenge were still able to reject the tumor, indicating high efficacy and long duration of the antitumor response.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] source

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    Premisenone given
    § Catumaxomab (Removab ® )

    No bispecific diabodies have been tested in clinical trials.

    “Surprisingly, no bispecific diabodies have been tested so far in clinical trials.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given
    § The New Generation: Recombinant bsAbs

    Advances in antibody engineering allowed production of small antibody fragments recapitulating the entire binding activity of the parent molecule.

    “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).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Catumaxomab (Removab ® )

    Diabodies can be expressed at high yields in bacteria and have been shown by crystallography to adopt several conformations.

    “These molecules can be expressed at high yields in bacteria and have been shown by crystallography experiments to adopt several conformations. 35”
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    Premisecitation
    § Catumaxomab (Removab ® )

    Moderate anti mouse and anti rat responses were seen in the majority of patients but do not seem to affect the efficiency of the treatment.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given
    § Catumaxomab (Removab ® )

    Tandem scFvs (TaFv) are two scFv fragments linked by an extra peptide linker that is expected to confer good flexibility to each fragment.

    “Tandem scFvs (TaFv) are two scFv fragments linked by an extra peptide linker that is expected to confer good flexibility to each fragment.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given
    § Bi20 (Lymphomun TM or fBTA05)

    CD20 is expressed on all stages of B cell development from pre-B cells through memory cells, but not on pro-B cells or plasma cells, making it an attractive target for the treatment of B cell malignancies.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Catumaxomab (Removab ® )

    Two other triomabs targeting melanoma-associated proteoglycans or melanoma-associated gangliosides (GD2 and GD3) are in preclinical studies as potential treatments for malignant melanoma.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] source

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  • May combine two claims.

    Premisecitation
    § Catumaxomab (Removab ® )

    T cell activation and tumor cell killing occurred in an entirely autologous setting, without additional effector cells, in 5 of 8 samples.

    “T cell activation and tumor cell killing occurred in an entirely autologous setting, i.e., without additional effector cells, in 5 of 8 samples.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] source

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  • May combine two claims.

    Interpretationreasoning
    § Ertumaxomab (Rexomun ® )

    The difference between ertumaxomab and trastuzumab can probably be explained by their modes of action: trastuzumab triggers NK-mediated ADCC, while ertumaxomab relies on T cell mediated killing and interaction between T cells and accessory cells, as demonstrated by release of proinflammatory cytokines IL-6, IFNγ and TNFα.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Ertumaxomab (Rexomun ® )

    Exposure to ertumaxomab led to efficient lysis of cells expressing very low amount of tumor antigen, whereas trastuzumab was completely ineffective even at high concentration.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] source

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  • May combine two claims.

    Premisecitation
    § Catumaxomab (Removab ® )

    rM28 spontaneously forms stable dimers and can induce T-cell activation and effective tumor-cell killing in vitro and in vivo without a signal through the TCR/CD3 complex.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given
    § Ertumaxomab (Rexomun ® )

    Ertumaxomab is a triomab targeting HER2, a well-characterized breast tumor marker that is also targeted by trastuzumab.

    “Ertumaxomab is triomab targeting HER2, a well-characterized breast tumor marker that is also targeted by trastuzumab (Herceptin).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given
    § BiTEs: Bispecific T Cell Engagers

    BiTEs are made by fusing an anti-CD3 scFv to an anti-TAA scFv via a short five residue peptide linker (GGGGS).

    “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).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § BiTEs: Bispecific T Cell Engagers

    This molecule demonstrated efficient cytotoxicity induced by extremely low concentrations (10-50 pg.mL-1, subpicomolar), at low effector:target ratio (2:1), in only four hours, without need for pre-stimulation of T cells or co-signaling.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Loffler A, 2000, Blood source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given
    § Bi20 (Lymphomun TM or fBTA05)

    Bi20 triomab utilizes the same hybrid Fc portion as catumaxomab and ertumaxomab, and targets CD20.

    “Bi20 triomab utilizes the same hybrid Fc portion as catumaxomab and ertumaxomab, and targets CD20.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data
    § The New Generation: Recombinant bsAbs

    Cumulative doses of several milligrams of blinatumomab were sufficient to lead to notable response in patients, whereas conventional antibody treatments such as rituximab consume gram amounts per treatment cycle.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § TF2

    In xenografted nude mice, TF2 produced exceptionally high tumor blood ratios ranging from 13 at 0.5 h to 395 at 24 h, with high tumor uptake of 30% ID/g, whereas levels in blood and normal tissues except kidney were <1% ID/g at 1 h after injection.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given
    § The New Generation: Recombinant bsAbs

    Blinatumomab, a murine anti-human CD3 x anti-human CD19, was the first BiTE developed and is the most advanced BiTE in clinical trials.

    “Blinatumomab, a murine antihuman CD3 x anti-human CD19 was the first BiTE developed and is the most advanced BiTE in clinical trials.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § The New Generation: Recombinant bsAbs

    Among all T cell subtypes, CD8+ effector memory CD45RO+ (TEM) and CD8+ effector memory CD45RA+ (TEMRA) contribute the most to BiTE activity, whereas naïve T cells do not contribute at all to killing efficiency.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given
    § The New Generation: Recombinant bsAbs

    MT110, an anti-human EpCAM x anti-human CD3 TaFv, was the second BiTE tested in clinical trial.

    “MT110, an anti-human EpCAM x anti-human CD3 TaFv, was the second BiTE tested in clinical trial and the”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given
    § The New Generation: Recombinant bsAbs

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § TF2

    Since MT110 does not activate murine T cells, tumor resident human T cells, being tolerized or anergized, could be reactivated and were present in sufficient number to eliminate the xenograft.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] source

      Not checked in the free run.

    • Rests on an assumption: MT110 does not activate murine T cells.

  • May combine two claims.

    Premiseown data
    § The New Generation: Recombinant bsAbs

    Thirteen out of 16 evaluable patients (81%) became MRD negative, with ongoing responses lasting for up to 47 weeks on May 25 2009.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § BiTEs: Bispecific T Cell Engagers

    Killing by BiTEs remains strictly target-cell dependent, and T cells cannot be activated in the absence of target cells, even at concentrations exceeding EC50 values by several thousand fold.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [48] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § The New Generation: Recombinant bsAbs

    The Phase 2 trial of blinatumomab in B-ALL was associated with significantly reduced toxicity compared to NHL patients at the same dose level, suggesting toxicity might be correlated to the number of target cells present in patients, rather than to the BiTE molecule itself.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § DNL Antibodies for Radioimmunotherapy

    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.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § TF2

    TF2 is a 157 kDa bsAb built using the DNL method, 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 strongly binds the hapten HSG.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § DNL Antibodies for Radioimmunotherapy

    DNL can be used to efficiently create any kind of bsAb, but was so far used to create bispecific molecules dedicated to radioimmunotherapy.

    “This can be used to efficiently create any kind of bsAb, but was so far used to create bispecific molecules dedicated to radioimmunotherapy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § The New Generation: Recombinant bsAbs

    Studies in chimpanzees showed repeated 2 h treatments with doses as low as 0.1 μg.kg-1 were well-tolerated and led to cumulative depletion of peripheral B cells due to fully reversible T cell activation.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § The New Generation: Recombinant bsAbs

    Because of its small size (60 kDa), blinatumomab has a short serum half life of several hours, requiring continuous intravenous infusion by portable mini-pumps.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Other DNL Based bsAbs in the Pipeline

    TF4 is a second bsAb built using the DNL method, directed against CD20 for the treatment of NHL.

    “TF4 is a second bsAb built using the DNL method, directed against CD20 for the treatment of NHL.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Other DNL Based bsAbs in the Pipeline

    PAM-4, the parental anti-MUC-1 antibody, binds a MUC1 epitope that is not detected in normal pancreas but is expressed in 87% of invasive pancreatic adenocarcinomas, including early stage 1 disease.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] source

      Not checked in the free run.

59 of 59

  • 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”
9 of 9

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?

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.

  • Kufer's 1995 study is cited as a 2008 clinical trial

    Minor

    The cited reference 44 is a 2008 paper by Fury and colleagues, not the 1995 Kufer study described in the text.

  • A 2008 blinatumomab result is cited to a 2000 paper

    Minor

    The text attributes the first result of a 2008 blinatumomab clinical study to reference 54, which lists a 2000 paper on a different class of bispecific antibody.

  • Lindhofer's 1995 paper is cited as a 2006 paper

    Minor

    The text cites reference 21 for a paper that Lindhofer and collaborators published in 1995, but reference 21 lists a 2006 paper by Schlereth and colleagues.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 6

  1. Chames P, 2009, Curr Opin Drug Discov Devel, 12, 276
  2. Hartmann F, 2001, Clin Cancer Res, 7, 1873
  3. Parsons S, 2009, J Clin Oncol, 27
  4. Muller D, 2007, Curr Opin Mol Ther, 9, 319
  5. Kischel R, 2008, Proc Am Assoc Cancer Res, 99, 2404
  6. McBride WJ, 2006, J Nucl Med, 47, 1678

Cited by

Sorted by citations

Related

Authors
Chames, P., & Baty, D.
Affiliations
Inserm (FR)
ORCID
Venue
mAbs
Publisher
Informa UK Limited
Published
2009-11
Volume
1
Issue
6
Pages
539-547
ISSN
  • 1942-0862 (ISSN-L)
  • 1942-0870
DOI
10.4161/mabs.1.6.10015
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
Locations
  • mAbs (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › 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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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