Bispecific Antibodies in Disease Treatment

Bispecific antibodies (bsAbs) constitute a class of artificial antibodies that can simultaneously bind to two different antigens or epitopes. They have emerged as a promising strategy for tumor immunotherapy, recruiting and activating immune cells to eliminate tumor cells, blocking multiple signaling pathways involved in tumor growth and survival. This approach overcomes the limitations of conventional monoclonal antibodies (mAbs). BsAbs come in various formats and structures, such as bispecific T cell engagers, dual-affinity re-targeting molecules, tandem diabodies (TandAbs), and crossmabs. Different methods, including chemical conjugation, hybrid hybridomas, genetic engineering, and single-chain variable fragment (scFv) fusion, can be employed for their production. BsAbs offer several advantages over conventional mAbs, such as high affinity, specificity, efficacy, low dose, low toxicity, and low resistance. They exert their antitumor effects through mechanisms like T cell-mediated cytotoxicity, natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC), dual blockade of signaling pathways, and enhanced tumor penetration. BsAbs have demonstrated promising results in treating hematologic malignancies and solid tumors, albeit facing challenges such as cytokine release syndrome (CRS), neurotoxicity, immune escape, and tumor heterogeneity.

Bispecific Antibodies in the Treatment of Hematologic Malignances

BsAbs have been widely used in the treatment of hematologic malignancies, such as multiple myeloma (MM), lymphoma, and leukemia. BsAbs can target tumor-associated antigens (TAAs) and immune cell receptors, such as CD3, CD16, and CD28, to induce immune cell activation and tumor cell lysis. BsAbs can also target two different TAAs or epitopes on the same tumor cell, to increase the specificity and efficacy of tumor recognition and elimination. BsAbs can overcome the resistance and relapse of hematologic malignancies to conventional therapies, such as chemotherapy, radiotherapy, and mAbs. One of the most successful examples of bsAbs in the treatment of hematologic malignancies is blinatumomab, a bispecific T cell engager molecule that binds to CD19 on B cell malignancies and CD3 on T cells. Blinatumomab has been approved by the FDA for the treatment of relapsed or refractory B cell precursor acute lymphoblastic leukemia (ALL) and minimal residual disease (MRD)-positive B cell precursor ALL. Blinatumomab has shown remarkable efficacy and safety in clinical trials. There are many other bsAbs in development or in clinical trials, such as epcoritamab, REGN1979, and teclistamab, that target different TAAs and immune cell receptors, such as CD19, CD20, CD22, CD30, CD38, and CD40. BsAbs have shown great potential and promise in the treatment of hematologic malignancies, but they also need to overcome some challenges and limitations, such as adverse events, immune escape, and tumor heterogeneity.

Bispecific Antibodies in the Treatment of Solid Tumors

BsAbs that target different antigens in the treatment of solid tumors are another promising strategy for cancer immunotherapy, as they can modulate different pathways or mechanisms involved in tumor growth and survival. Some of the common antigens that are targeted by BsAbs in solid tumors are EGFR, HER2, PSMA, and CEA, which are overexpressed or mutated in various types of cancers, such as lung cancer, breast cancer, prostate cancer, and colorectal cancer. By simultaneously binding to these antigens and other molecules, such as CD3, CD16, or immune checkpoint inhibitors, BsAbs can achieve different effects, such as T cell recruitment, NK cell activation, dual receptor blockade, or synergistic inhibition. For example, BsAbs that target EGFR and CD3 can recruit and activate T cells to the tumor site, thereby inducing the T cell-mediated cytotoxicity and killing of the tumor cells that express EGFR. Several BsAbs that target EGFR and CD3 have shown promising results in clinical trials for solid tumors, such as ZW25, which is a bispecific IgG that binds to two distinct epitopes on HER2, and MGD009, which is a bispecific diabody that binds to B7-H3 and CD3.

References

1. Kontermann RE, et al. Bispecific antibodies. Drug Discov Today. 2015 Jun;20(7):838-47.
2. Spiess C, et al. Alternative molecular formats and therapeutic applications for bispecific antibodies. Mol Immunol. 2015 Oct;67(2 Pt A):95-106.
3. Bacac M, et al. CEA TCB: A novel head-to-tail 2:1 T cell bispecific antibody for treatment of 4. CEA-positive solid tumors. Oncoimmunology. 2016 Sep 2;5(10):e1203498.
4. Fan G, et al. Bispecific antibodies and their applications. J Hematol Oncol. 2015 Dec 29;8:130.
5. Zhang Y, et al. Bispecific Antibodies: A New Era of Cancer Immunotherapy. Front Immunol. 2020 Dec 18;11:607414.
6. Li J, et al. Bispecific antibodies in solid tumors: design, challenges and clinical application. Signal Transduct Target Ther. 2020 Nov 6;5(1):247.