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Bispecific antibodies (bsAbs) act as a biophysical bridge between two antigens, enabling diverse mechanisms of action in vivo, such as T cell and NK cell engagement, tumor targeting, and immune modulation. While widely explored in oncology, bsAbs—particularly T-cell engagers—are also emerging as promising therapies for autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus, where they selectively target B cells and inflammatory mediators to restore immune balance (Blanco, Domínguez-Alonso, & Alvarez-Vallina, 2021, Dahlén, Veitonmäki, & Norlén, 2018, Zhao, 2020).
Applications of Bispecific Antibodies
BsAbs were first used in cancer therapy to redirect T cells to tumor cells, recognizing tumor-associated antigens (TAA) and triggering T cell-mediated cytotoxicity (Dahlén, Veitonmäki, & Norlén, 2018). A growing area in bispecific/multispecific antibody development involves redirecting NK cells to tumors, leading to "bispecific killer cell engagers" (BiKEs) and "trispecific killer cell engagers" (TriKEs) (Blanco, Domínguez-Alonso, & Alvarez-Vallina, 2021). BsAbs can also simultaneously target two distinct TAA/TSA (tumor-specific antigens), enhancing specificity while blocking two tumor signaling pathways, reducing immune tolerance, and mitigating drug resistance.
BsAbs can also improve clinical outcomes by targeting immune checkpoint molecules—blocking co-inhibitory receptors, activating co-stimulatory receptors, or modulating both. Another key application is targeting the tumor microenvironment, which plays a critical role in immune evasion and progression.
In autoimmune diseases, bsAbs can help restore immune balance by depleting T or B cells, inhibiting T cell activation or differentiation, or neutralizing proinflammatory cytokines, offering new therapeutic strategies for conditions like rheumatoid arthritis and lupus (Zhao, 2020).
For neurological disorders, particularly blood-brain barrier (BBB) transport, bsAbs engineered to cross the BBB can target neural antigens for treating neurodegenerative diseases such as Alzheimer's and Parkinson’s, improving drug delivery efficiency while minimizing side effects (Labrijn et al., 2019).
Bispecific Antibodies: A Mechanistic Overview of the Pipeline (Source: Labrijn et al., 2019)
With the rapid expansion of bsAb therapeutics, an increasing number of candidates are advancing into clinical trials for both cancer and immune disorders. To accelerate preclinical development, Biocytogen offers a comprehensive platform featuring validated animal models and bioassays for target validation, efficacy assessment, and safety profiling, ensuring robust data for clinical translation.
Preclinical Animal Models for BsAb Evaluation
Biocytogen offers a diverse portfolio of drug-targeted humanized and immune-reconstituted mouse models to support the preclinical evaluation of bsAbs across various disease areas.
Featured Drug-Targeted Humanized Mouse Models
Featured Immune System-Reconstituted B-NDG Models
Case Study
Antitumor activity of anti-human CD3×HER2 bsAb in B-hCD3E/hHER2 mice and PBMC-reconstituted CDX models (A) Anti-human CD3×HER2 bsAb (Ab1, provided by a client) inhibited B-hHER2 MC38 plus tumor growth in homozygous B-hCD3E/hHER2 mice. B-hHER2 MC38 plus cells were implanted subcutaneously, and treatment began when tumors reached ~100 mm³. (B) Human PBMC-reconstituted B-NDG mice were implanted with NCI-N87 cells, and anti-human CD3×HER2 bsAb treatment significantly inhibited tumor growth.
Evaluation of BACE1×TFR1 bsAbs for BBB penetration in B-hTFR1 mice
Evaluation of BACE1×TFR1 bsAb variants in B-hTFR1 mice, assessing neuronal uptake (top), brain parenchymal distribution, and BBB penetration (bottom). (Data from client)
In Vitro Bispecific Antibody Evaluation Services at Biocytogen
Biocytogen offers fast, reliable, and reproducible in vitro studies to evaluate the function and mechanism of action of bsAbs using advanced flow cytometry and cell-based platforms. Our assays include target validation, intracellular signal transduction analysis, Fc effector function assessments (ADCC, ADCP, CDC), safety evaluation, and more.
Case Study
Cell-based functional analysis of CD3-based bsAb blinatumomab (A) Blinatumomab promoted the proliferation of T cells co-cultured with Daudi cells in a dose-dependent manner. (B) Blinatumomab showed dose-dependent cytotoxicity at a 10:1 Daudi-to-T cell ratio. (C-D) Blinatumomab significantly increased IFN-γ and IL-2 secretion in a dose-dependent manner.
Contact us today to explore how Biocytogen’s expertise can fast-track your BsAb therapeutic development!
References
Labrijn, Aran F., et al. "Bispecific antibodies: a mechanistic review of the pipeline." Nature reviews Drug discovery 18.8 (2019): 585-608.
Blanco, Belén, Carmen Domínguez-Alonso, and Luis Alvarez-Vallina. "Bispecific immunomodulatory antibodies for cancer immunotherapy." Clinical Cancer Research 27.20 (2021): 5457-5464.
Dahlén, Eva, Niina Veitonmäki, and Per Norlén. "Bispecific antibodies in cancer immunotherapy." Therapeutic advances in vaccines and immunotherapy 6.1 (2018): 3-17.
Zhao, Qi. "Bispecific antibodies for autoimmune and inflammatory diseases: clinical progress to date." BioDrugs 34.2 (2020): 111-119.
