Clinical Pharmacology and Translational Aspects of Bispecific Antibodies
Open accessAbstract
Development of bispecific antibodies (BsAbs) as therapeutic agents has recently attracted significant attention, and investments in this modality have been steadily increasing. This review discusses challenges, and suggestions to overcome them, associated with the development of BsAbs, specifically those pertaining to clinical pharmacology, pharmacometrics, and bioanalysis. These challenges and possible solutions are discussed by presenting several case studies of BsAbs that have gained regulatory approval or that are currently in clinical development. BsAbs, also termed "dual-targeting" or "dual-specificity" antibodies, have the ability to bind two different targets on the same or different cell(s); the targets may be cell-surface receptors or soluble ligands, as shown in Figure 1. These dual-nature antibodies have key advantages that can potentially enhance therapeutic efficacy compared with monotherapy or traditional combination therapies by: i) simultaneously blocking two different targets or mediators that have a primary role in the disease pathogenesis; ii) inducing cell signaling pathways (e.g., proliferation or inflammation); iii) retargeting to mediate antibody-dependent cell-mediated cytotoxicity (ADCC); iv) avoiding the development of resistance and increasing antiproliferative effects, specifically in oncology; and v) temporarily engaging a patient's own cytotoxic T cells to target cancer cells, thus activating cytotoxic T cells to cause tumor lysis (e.g., bispecific T-cell engagers (BiTE)). Various designs for BsAb molecules (a) Dimers inhibition: BsAbs can bind to two receptors/targets (HER2/HER3, HER2/HER4) on the same cell (e.g., MM-111); (b) Dual inhibition: BsAbs can inhibit two different cytokines simultaneously, for example, COVA322 that inhibits TNF-α and IL17A; (c) Triomabs: The antigen binding site binds to target cell receptors (EpCAM, HER2, or CD20) and the T-cell receptors (CD3). The heavy chain site binds to NK cells or dendritic cells or macrophages/phagosome (e.g., catumaxomab, ertumaxomab, FBTA05); (d) Two-ligand inactivation: two arms bind to different ligands on different cells belonging to the same population, such as DLL4 x VEGF, TNF-α x IL17A, IL4 x IL13 (e.g., OMP-305B83, COVA322, SAR156597); (e) Transmembrane/transcytosis: The BsAbs are designed specifically to cross the barriers/membrane via receptor transport (transferrin receptor) and bind to enzymes/receptors (BACE1) on the other side; (f) BiTE antibody construct: These are designed to bridge T cells and target cells by binding to CD3/CD28 or CD19/CD20/CD22/CEA/EpCAM, respectively (e.g., blinatumomab, MEDI-565, MT110). The examples mentioned above can be found in Table 2 for further information. BACE1, β-secretase 1; BiTE, bispecific T-cell engagers; BsAbs, bispecific antibodies; DDL4, delta-like ligand 4; EpCAM, epithelial cell adhesion molecule; HER, human epidermal growth factor receptor; IL, interleukin; NK, Natural Killer; TNF-α, tumor necrosis factor-alpha; VEGF, vascular endothelial growth factor. Traditional combination therapies using monoclonal antibodies (mAbs) can also modulate multiple therapeutic targets. However, the development of mAbs presents challenges not encountered with BsAbs. For example, regulatory agencies have established stringent criteria for the codevelopment of new drugs that are intended for use as combination therapies. The sponsor has to demonstrate i) the rationale for use of the combination therapy rather than individual treatments; ii) a strong justification for why the individual drugs cannot be studied and developed independently; iii) that the nonclinical and clinical studies provide adequate evidence showing that the combination therapy provides significant therapeutic gain; and iv) a reasonable toxicity profile and more durable response than the monotherapy and existing standard of care.1 These guidelines can potentially make the drug development process for combination therapy lengthy and expensive. Conversely, BsAbs are able to address the biology associated with two different targets simultaneously via a similar regulatory pathway as that required for with a single-target mAb. BsAbs may therefore offer the opportunity to benefit patients more quickly, and to access less costly development routes than can be afforded via classic combination therapies. BsAbs also offer the opportunity to modulate unexplored biology in novel ways that may not be possible with single-target mAbs. Avidity is defined as the measure of the overall strength of binding of an antigen with multiple antigenic determinants to multivalent antibodies. According to the "avidity hypothesis," BsAbs may surpass combination therapy in terms of both biology and mechanistic behavior as a result of this theoretical concept. The theory states that avidity increases when two receptors are bound to a target cell, leading to efficacy greater than which could be expected from the additive combination each single mAb.
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The MABEL approach was used more frequently in recent years.
“The MABEL approach was used more frequently in recent years, reflecting the increasing repertoire of immune modulators and the recognition of translational insufficiency for this family of molecules.75”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [75]
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Targeting Solid Tumors Using CD3 Bispecific Antibodies
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- Authors
- Trivedi, A., Stienen, S., Zhu, M., Li, H., Yuraszeck, T., Gibbs, J., Heath, T., Loberg, R., & Kasichayanula, S.
- Affiliations
- Amgen (United States) (US)
- Amgen (Germany) (DE)
- Corresponding author
- Trivedi, A
- Venue
- Clinical and Translational Science
- Publisher
- Wiley
- Published
- 2017-03-15
- Volume
- 10
- Issue
- 3
- Pages
- 147-162
- ISSN
- 1752-8054 (ISSN-L)
- 1752-8062
- PMC
- PMC5421745
- OpenAlex
- W2602965251
- Cited by
- 76
- References
- 77
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 4 · 2023: 6 · 2022: 7 · 2021: 11 · 2020: 14 · 2019: 5 · 2018: 16 · 2017: 3
- FWCI
- 1.57
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Clinical and Translational Science (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Amgen
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › Biosimilars and Bioanalytical Methods
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- bispecific antibodies, clinical pharmacology, pharmacometrics, bioanalysis, antibody-dependent cellular cytotoxicity, bispecific T-cell engagers, MM.111, catumaxomab, pharmacokinetics, pharmacodynamics, regulatory approval, translational research, cancer immunotherapy
- MeSH terms
- Drug Development, Animals, Humans, Antibodies, Bispecific, Risk Assessment, Translational Research, Biomedical, Patient Safety
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