Bispecific antibodies for the treatment of breast cancer

Abstract

Introduction: There are more than two dozen bispecific antibodies (BsAbs) in development with a variety of designs which are relevant to breast cancer. The field of BsAbs for breast cancer includes agents that co-direct immune recognition of the cancer cell, target unique cancer antigens, and target the microenvironment. BsAbs are being developed for use as antibody-drug conjugates and as homing signals for engineered T-cells.

Areas covered: This review covers potential targets for bispecific antibodies, agents in pre-clinical development, agents in clinical trials, combinatorial therapies, and future directions.

Expert opinion: There is no BsAb approval expected for breast cancer in the near term, but late-stage trials are underway. Future BsAb roles in breast cancer are possible given unmet needs in estrogen receptor+ disease, residual disease, and de-escalating chemotherapy use. The HER2+ space shows hints of success for BsAbs, but is already crowded. Areas of unmet need still exist.

Keywords: Bispecific antibody; breast cancer; cellular therapy; clinical trials; immunotherapy.

Figure 1:

Mechanisms involved in bispecific antibody mediated cytotoxicity. A: Non-MHC restricted perforin/granzyme B mediated killing by redirected T cells. B: Antibody dependent cellular cytotoxicity mediated by Fc-recepter binding of bipecific antibody, NK cell and effector T cell. C: Antibody dependent cellular cytotoxicity mediated by T effector cell and monocyte.

Figure 2:

Various bispecific antibody formats are shown as whole antibody molecules or engineered antibody derivatives containing variable regions of heavy and light chains. The heavy chains targeting CD3 and TAA are depicted in dark blue and red respectively. The light chains targeting CD3 and TAA are depicted in light blue and pink, respectively BiTE = Bispecific T cell engager; Chemical heteroconjugate = two antibodies linked; DART= Dual-affinity retargeting bispecific antibody; Trifunctional Antibody: quadroma fusion with Fc-binding portion; TanB; bispecific tetravalent chimeric antibody construct; BIKE: Bispecific killer cell engagers; Diabody: basic construct of genetically fusing variable domains of the heavy and light chains with linkers. The heavy chains targeting CD3 and TAA are depicted in dark blue and red respectively. The light chains targeting CD3 and TAA are depicted in light blue and pink, respectively.

Figure 3:

The proposed mechanism of BsAb armed T cell therapy. In this figure, the BsAb armed T cells are a population of T cells collected by apheresis and expanded ex vivo. Those T cells are then armed with an anti-CD3 BsAb with secondary specificity for a tumor antigen. Upon re-infusion into the body, the BsAb armed T cells preferentially collocate at the site of tumor antigen presence where cancer cells exist in the body. Th1 cytokine release ensues and cooperates in tumor cytolysis. The secondary process of additional tumor antigen release and presentation occurs and results in specific activation of endogenous, non-BsAb-armed CD4 and CD8 T cells and an expansion of tumor specific immune response as shown at the bottom right.