Discovery Strategies to Maximize the Clinical Potential of T-Cell Engaging Antibodies for the Treatment of Solid Tumors

Abstract

T-cell Engaging bispecific antibodies (TcEs) that can re-direct cytotoxic T-cells to kill cancer cells have been validated in clinical studies. To date, the clinical success with these agents has mainly been seen in hematologic tumor indications. However, an increasing number of TcEs are currently being developed to exploit the potent mode-of-action to treat solid tumor indications, which is more challenging in terms of tumor-cell accessibility and the complexity of the tumor microenvironment (TME). Of particular interest is the potential of TcEs as an immunotherapeutic approach for the treatment of non-immunogenic (often referred to as cold) tumors that do not respond to checkpoint inhibitors such as programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) antibodies. This has led to considerable discovery efforts for, firstly, the identification of tumor selective targeting approaches that can safely re-direct cytotoxic T-cells to cancer cells, and, secondly, bispecific antibodies and their derivatives with drug-like properties that promote a potent cytolytic synapse between T-cells and tumor cells, and in the most advanced TcEs, have IgG-like pharmacokinetics for dosing convenience. Based on encouraging pre-clinical data, a growing number of TcEs against a broad range of targets, and using an array of different molecular structures have entered clinical studies for solid tumor indications, and the first clinical data is beginning to emerge. This review outlines the different approaches that have been taken to date in addressing the challenges of exploiting the TcE mode-of-action for a broad range of solid indications, as well as opportunities for future discovery potential.

PAX8 lineage-driven T cell-engaging antibody for the treatment of high-grade serous ovarian cancer

“…The narrow therapeutic index of T cell bispeci c antibodies has been a major challenge for the successful development of TCBs against solid tumor targets such as CEA, PSMA and HER2 (10)(11)(12). Recent single agent clinical responses demonstrated by the anti-DLL3xCD3 (AMG757) in small cell lung cancer and by the anti-MUC16xCD3 (REGN4018) in advanced ovarian cancers have demonstrated clinical proof-of-concept for this modality for targets with tumor-restricted expression pro les similar to LYPD1 (13,14).…”

“…BiTEs and traditional CD3 bispeci c antibodies targeting BCMA have similarly demonstrated 70% clinical response rates in multiple myeloma patients (8,9). However, in solid tumors, the narrow therapeutic index has been a major challenge for the successful development of the T cell bispeci c antibodies against targets such as CEA, PSMA and HER2 (10)(11)(12). Despite these challenges, CD3 T cell-engaging antibodies targeting largely tumor-restricted targets are emerging as potent forms of immunotherapy in advanced-stage solid tumors of high unmet medical need.…”

Recent Advances in the Molecular Design and Applications of Multispecific Biotherapeutics

“…Among them, there are three approved bispecific antibodies (catumaxomab (Removab TM ), blinatumomab (Blincyto ® ), emicizumab (Hemlibra ® )), one approved antibody binding fragment fusion with immunotoxin (Lumoxiti TM ), and nine approved antibody-drug conjugates (gemtuzumab ozogamicin (Mylotarg ® ), brentuximab vedotin (Adcetris ® ), ado-trastuzumab emtansine (Kadcyla ® ), inotuzumab ozogamicin (Besponsa ® ), enfortumab vedotin (Padcev TM ), fam-trastuzumab deruxtecan-nxki (Enhertu ® ), polatuzumab vedotin-piiq (Polivy TM ), belantamab mafodotin-blmf (Blenrep TM ), sacituzumab govitecan (Trodelvy TM )). These successes, along with nearly 200 multispecific biotherapeutic candidates in the clinical pipelines [3][4][5][6]10,[16][17][18][19][20][21][22][23][24][25][26][27][28], indicate that multispecific bio-therapeutics are promising molecules. However, discovering and developing them into an approved product is challenging and requires extensive efforts in engineering and development.…”

“…One novel subclass of tetherbody-like multispecific biotherapeutics drugs is the condition-activated tetherbody that can enrich the active drugs in a particular location through the design of conditional activation. The conditional activation mechanisms take advantage of special conditions in tumor microenvironment such as increased levels of specific proteases [184], ATP [185,186], and others [20]. Because the presence of tumor antigen in healthy tissues can cause on-target toxicity by ADCs or bsTCEs, Probodies TM (CytomX) with a protease-cleavable peptide linker and a masking peptide can presumably remain inert until proteolytically activated locally in disease tissues [184].…”

“…The topic of multispecific biotherapeutics represents a fast-growing field regarding formats, design strategies, and applications. A number of outstanding review articles have been written on this topic or related themes for the past few years [2][3][4][5][6][9][10][11][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. This review summarizes comprehensively the recent advances in molecular design and applications of the multispecific biotherapeutics from the early stages of research discovery to the late stages of clinical and regulatory development.…”