Bispecific antibodies in cancer immunotherapy

Abstract

Among antibody-based cancer therapies, bispecific antibodies (biAbs) have gained momentum in preclinical and clinical investigations following the regulatory approvals of the trailblazing T-cell engaging biAb (T-biAb) blinatumomab. Discussed herein are recent strategies that aim at boosting the potency and mitigating the toxicity of T-biAbs, broadening their therapeutic utility from hematologic to solid malignancies, and generating T-biAbs in situ. In cancer immunotherapy, T-biAbs are facing fierce competition with chimeric antigen receptor T cells (CAR-Ts), a battle for clinical and commercial viability that will be closely watched. However, innovative combinations of T-biAbs and CAR-Ts have also transpired. NK-cell engaging biAbs (NK-biAbs) are reemerging as an alternative that addresses liabilities of T-biAbs. Beyond NK-biAbs, other biAbs designed to recruit cellular and molecular components of the innate immune system will be covered in this reflection on new tools, technologies, and targets.

Figure 1.. Conventional and in situ delivery of T-biAbs.

T-biAbs mediate potent and selective cytotoxicity by recruiting and activating T cells (blue) with one arm (also blue) and targeting tumor cells (orange) with the other arm (also orange). Note that the blue arm typically engages CD3ε of the TCR complex whereas the orange arm targets one of many tumor cell surface receptors that can be restricted to the tumor cell (tumor-specific antigen, TSA) or shared with expandable healthy cells (tumor-associated antigen, TAA). (a) Conventional T-biAbs in tandem scFv format as shown or other low molecular weight assemblies without Fc domain are administered as continuous intravenous infusion due to their short circulatory half-lives. Alternatively, they can be administered as mRNA via viral or nonviral transduction of liver and muscle cells. (b) T-biAbs with Fc domain, as exemplified here by a scFv-Fc format, have long circulatory half-lives and are administered as bolus injection similar to conventional mAbs. (c) As part of their ex vivo production, CAR-T cells can be transduced with a T-biAb expression cassette for in situ delivery, facilitating a one-two punch with the CAR-T targeting a TSA and the T-biAb targeting a TAA. (d) OVs, as exemplified here by an adenovirus, can deliver a T-biAb expression cassette to tumor cells. In addition to programming tumor cells for T-biAb production, inflammation triggered by the oncolytic activity of the OV can turn cold into hot tumors, i.e. mitigate immunosuppression in the tumor environment to augment the potency of the T-biAb.