Principles and Current Clinical Landscape of Multispecific Antibodies against Cancer

Abstract

Building upon the resounding therapeutic success of monoclonal antibodies, and supported by accelerating progress in engineering methods, the field of multispecific therapeutic antibodies is growing rapidly. Over 140 different molecules are currently in clinical testing, with excellent results in recent phase 1–3 clinical trials for several of them. Multivalent bispecific IgG-modified formats predominate today, with a clear tendency for more target antigens and further increased valency in newer constructs. The strategies to augment anticancer efficacy are currently equally divided between disruption of multiple surface antigens, and additional redirection of cytotoxic T or NK lymphocytes against the tumor. Both effects complement other modern modalities, such as tyrosine kinase inhibitors and adoptive cell therapies, with which multispecifics are increasingly applied in combination or merged, for example, in the form of antibody producing CAR-T cells and oncolytics. While mainly focused on B-cell malignancies early on, the contemporary multispecific antibody sector accommodates twice as many trials against solid compared to hematologic cancers. An exciting emerging prospect is the targeting of intracellular neoantigens using T-cell receptor (TCR) fusion proteins or TCR-mimic antibody fragments. Considering the fact that introduction of PD-(L)1 inhibitors only a few years ago has already facilitated 5-year survival rates of 30–50% for per se highly lethal neoplasms, such as metastatic melanoma and non-small-cell lung carcinoma, the upcoming enforcement of current treatments with “next-generation” immunotherapeutics, offers a justified hope for the cure of some advanced cancers in the near future.

Engineering SARS-CoV-2 cocktail antibodies into a bispecific format improves neutralizing potency and breadth

“…The IgG-(scFv) 2 design is a promising platform and has been used for developing more than ten-clinical stage bsAb candidates 33 . Antibody 14-H-06 expresses in high yield (>0.5 g/L) in transient expression and assembles homogenously, suggesting suitable early developmentability profiles.…”

Glycans as Targets for Drug Delivery in Cancer

“…Regardless, given their high specificity to tumor-derived antigens, mAbs represent extremely versatile platforms for the targeted delivery of cytotoxic drugs to the tumor site, such as conventional chemotherapeutic agents (antibody-drug conjugates (ADCs)), while reducing the occurrence of off-target toxicity. More recently, therapeutic antibodies have been engineered to bind to more than just two structurally identical epitopes (multi-valency), as well as to structurally distinct epitopes (multi-specificity) [ 76 ]. Such is the example of bi-specific T cell Engagers (BiTEs), which aim at stimulating anti-tumor immune-mediated synapses by simultaneously targeting a tumor antigen and the activating T cell receptor CD3 [ 77 ].…”

Immune escape mechanisms and therapeutic approaches in cancer: the cancer-immunity cycle

“… 80 Further, bispecific and trispecific T-cell engager (BiTE, TriTE) as well as bispecific and trispecific killer cell engager (BiKE, TriKE) multispecific antibodies (msABs) are linkers between endogenous cytotoxic T/NK cells and antigens expressed by cancer cells with two or three binding domains, respectively. 81 , 82 The consecutive binding of the cytotoxic T/NK cells and the cancer antigens leads to T-cell proliferation and potentiation of the T-cell-mediated immune response and increased tumor specificity. 82 MsABs are currently under clinical investigation in Phase I–III trials and bear the potential to overcome escape mutations and to access personalized immunotherapy approaches (NCT04631601, NCT03319940, NCT03214666; Table 1 ).…”