Resources>Blog>
Mechanisms of Action of Bispecific Antibodies in Cancer Therapy
Mechanisms of Action of Bispecific Antibodies in Cancer Therapy
Biointron2024-10-08Read time: 6 mins
Bispecific antibodies (bsAbs) are a class of engineered therapeutic molecules designed to engage two different epitopes or antigens simultaneously, providing them with unique functionalities that go beyond traditional monoclonal antibodies. By targeting two distinct antigens, bsAbs can connect immune cells with tumor cells, block multiple signaling pathways, or engage immune checkpoint receptors. This flexibility allows bsAbs to be used in a variety of therapeutic strategies, including immune cell engagement, dual immune checkpoint modulation, and signaling pathway blockade.1
Immune Cell Engagers
One of the most significant applications of bsAbs is their role as immune cell engagers, which can direct immune cells to recognize and destroy cancer cells. The most well-known of these are bispecific T cell engagers (TCEs). These bsAbs are designed to link tumor cells with T cells by simultaneously binding the CD3 receptor on T cells and a tumor-associated antigen (TAA) on cancer cells. This interaction activates T cells, particularly cytotoxic T cells, which then target and kill the tumor cells. Notably, TCE-induced killing occurs independently of major histocompatibility complex (MHC) antigen presentation, making TCEs especially valuable in tumors that have lost MHC expression, a common cancer resistance mechanism.
For example, TCEs such as glofitamab, used in B cell non-Hodgkin lymphoma (B-NHL), promote not only the direct killing of tumor cells but also reshape the tumor microenvironment (TME). This is achieved through the secretion of cytokines and chemokines, leading to increased infiltration of immune cells, including additional T cells. However, recent research in multiple myeloma (MM) has shown that T cell activation by certain TCEs may still depend on peptide-MHC class I interactions, suggesting that MHC presentation may be necessary for optimal TCE function in some cancers.
In addition to TCEs, bispecific killer cell engagers (BiKEs) redirect natural killer (NK) cells toward tumor cells. Unlike T cells, NK cells do not require antigen-specific receptors and can attack cancer cells independently of antigen presentation. BiKEs, such as AFM13 (CD30xCD16A), which targets CD30+ lymphomas, have shown promising clinical results by leveraging NK cells' ability to mediate antibody-dependent cellular cytotoxicity (ADCC). NK cells are particularly effective against MHC I-deficient tumors, providing an additional therapeutic strategy where immune evasion is a concern.
Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by blocking inhibitory signals on T cells, thereby enhancing the immune response against tumors. However, many tumors develop resistance to ICIs, either through compensatory upregulation of other inhibitory pathways or by adapting the tumor microenvironment. Bispecific antibodies that simultaneously target two immune checkpoints offer a solution to this problem by blocking multiple inhibitory pathways at once.
For instance, bsAbs targeting both PD-1 and CTLA-4 on T cells, such as volrustomig and cadonilimab, preferentially target tumor-infiltrating lymphocytes (TILs) over peripheral T cells, reducing the risk of off-target toxicities. This avidity-based selection helps concentrate the therapeutic effect on tumor-specific immune cells while minimizing systemic immune activation. Such dual checkpoint blockade can improve the anti-tumor immune response while preventing the compensatory upregulation of alternative checkpoints, a common escape mechanism in single-agent ICI therapies.
An additional advantage of dual-targeting bsAbs, like FS118 (LAG-3 × PD-L1), is their ability to reduce the expression of both targets simultaneously. By promoting internalization and degradation of LAG-3 and PD-L1, FS118 more effectively disrupts tumor immune evasion mechanisms than monotherapies, which may inadvertently increase the expression of these checkpoints. This makes dual immune checkpoint blockade with bsAbs a promising strategy to overcome resistance and improve durable responses in cancer patients.
Signaling Pathway Blockade
Another application of bsAbs lies in blocking cancer signaling pathways. Many cancers rely on aberrant signaling to drive tumor growth, angiogenesis, and metastasis. By simultaneously blocking two different signaling pathways, bsAbs can inhibit multiple aspects of tumor progression while reducing the likelihood of resistance.
One example is amivantamab, which targets both EGFR and MET in non-small cell lung cancer (NSCLC). This bsAb prevents the activation of downstream signaling cascades, such as those involved in cell proliferation and survival, while also promoting receptor degradation, thus inhibiting resistance mechanisms that often arise during treatment with tyrosine kinase inhibitors (TKIs). Amivantamab has shown efficacy in overcoming resistance in EGFR-mutated NSCLC, which is often driven by the upregulation of alternative pathways, such as MET signaling.
Another approach to signaling pathway blockade involves targeting angiogenesis, a process critical to tumor survival. ABT-165, a bsAb that targets both VEGF and Delta-like ligand 4 (DLL4), effectively disrupts tumor blood supply by inhibiting both pathways. This dual blockade leads to reduced tumor vessel perfusion and tumor growth inhibition, outperforming single-target anti-angiogenic therapies.
Bispecific Antibodies for In Vivo Research
Biointron’s catalog products for in vivo research can be found at Abinvivo, where we have a wide range of Bispecific Antibodies, Antibody-Drug Conjugates, Benchmark Positive Antibodies, Isotype Negative Antibodies, and Anti-Mouse Antibodies. Contact us to find out more at info@biointron.com or +86 400-828-8830 / +1(732)790-8340.
References:
Herrera, M., Giulia Pretelli, Desai, J., Garralda, E., Siu, L. L., Steiner, T. M., & Au, L. (2024). Bispecific antibodies: advancing precision oncology. Trends in Cancer. https://doi.org/10.1016/j.trecan.2024.07.002
Abinvivo offers a range of antibody products for in vivo research, each designed to meet specific research needs and applications in preclinical studies and antibody development.
Complementarity-determining regions (CDRs) are polypeptide sequences within antibodies (Abs) that dictate the specific recognition and binding of antigens. Antibodies are part of the human immune response and are composed of two heavy and two light protein chains. These chains are divided into variable (V) and constant (C) regions, with the V region responsible for binding to unique antigens.
Antigens are molecules or molecular structures that are recognized by the immune system, particularly by antibodies, T cells, and B cells. The immune response to an antigen varies depending on the antigen type and the part of the immune system involved. This interaction underpins immunity by helping the body distinguish between self and non-self molecules.