Revolutionizing cancer immunotherapy: unleashing the potential of bispecific antibodies for targeted treatment

Abstract

Recent progressions in immunotherapy have transformed cancer treatment, providing a promising strategy that activates the immune system of the patient to find and eliminate cancerous cells. Bispecific antibodies, which engage two separate antigens or one antigen with two distinct epitopes, are of tremendous concern in immunotherapy. The bi-targeting idea enabled by bispecific antibodies (BsAbs) is especially attractive from a medical standpoint since most diseases are complex, involving several receptors, ligands, and signaling pathways. Several research look into the processes in which BsAbs identify different cancer targets such angiogenesis, reproduction, metastasis, and immune regulation. By rerouting cells or altering other pathways, the bispecific proteins perform effector activities in addition to those of natural antibodies. This opens up a wide range of clinical applications and helps patients with resistant tumors respond better to medication. Yet, further study is necessary to identify the best conditions where to use these medications for treating tumor, their appropriate combination partners, and methods to reduce toxicity. In this review, we provide insights into the BsAb format classification based on their composition and symmetry, as well as the delivery mode, focus on the action mechanism of the molecule, and discuss the challenges and future perspectives in BsAb development.

SpyMask enables combinatorial assembly of bispecific binders

“…The SpyMask platform offers a plug-and-play approach in which the antigen-binding building blocks exist in a common format, fused to the commonly employed SpyTag peptide or its subsequent generations 25 , 28 . Unlike standard approaches to bispecific assembly 1 , 2 , SpyMask eliminates the need to clone and express each pair of binding proteins into more than one format. Neither SpyTag nor SpyCatcher require any cysteines and the overall assembly is ligated through amide bonds 25 , so SpyMask avoids the careful optimization and instability that may arise from bispecific assembly relying on disulfide bond reduction and oxidation.…”

“…Only a small fraction of the surfaceome (estimated at 2,886 different proteins across human cells) 67 has been explored in terms of its potential for bispecific drug generation in academia and industry 2 . Even for an individual member of the surfaceome, different cellular effects are often obtained by binders that recognize different sites 8 , 52 .…”

“…bacterially-derived non-immunoglobulin scaffolds such as affibodies have shown promising results for sustained therapy in clinical trials 70 . For fitting into existing production and purification pipelines 13 , the most likely route would be to use SpyMask-derived bispecifics to identify promising hits (including with deep phenotypic analysis by multiparameter flow cytometry, high-throughput microscopy or RNAseq) 71 , 72 and then to reformat the binders into a classic Fc bispecific as a lead for future clinical development 2 , 73 .…”

“…Bispecific antibodies are biological matchmakers, bringing together two different target molecules or two different parts of the same target 1 , 2 . Bispecifics have had clinical success in cancer therapy by directing cytotoxic T cells to cancer-specific antigens 1 , 2 . There are also approved bispecific therapeutics that bridge proteins on the surface of the same cell 3 , 4 .…”

“…The most common routes to generate bispecifics depend upon the rearrangement of IgG architecture, particularly through knob-into-hole generation of heterodimeric Fc domains 10 , or disulfide bond shuffling for Fab-arm exchange 11 – 13 , leading to many important clinical successes 2 . Alternative bispecific pairing has been achieved by conjugating the two binders using sortase 14 , transglutaminase 15 , click chemistry 16 or split inteins 17 .…”