Sean P. Sullivan

Bispecific antibodies (bsAbs) and bispecific antibody–drug conjugates (bsADCs) represent promising classes of emerging targeted therapeutics with the potential to overcome tumor heterogeneity and resistance in colorectal cancer (CRC). BsAbs can simultaneously engage multiple tumor antigens or immune cells or bind two distinct epitopes within a single target, enabling mechanisms of action beyond the capabilities of monoclonal antibodies. Bispecific T cell engagers facilitate targeted destruction of tumors through immune cell recruitment, while dual immune checkpoint inhibitors enhance immune activation by blocking T cell inhibitory signals. Furthermore, bsAbs can mediate dual signaling pathway inhibition through binding multiple receptor tyrosine kinase receptors or other tumor cell surface proteins. BsADCs integrate the dual-antigen recognition of bsAbs with targeted payload delivery, utilizing receptor-mediated endocytosis to deliver potent cytotoxic payloads selectively to CRC cells, while minimizing systemic toxicity. Recent advances in bsAb engineering, linker chemistry, site-specific conjugation, and payload design have accelerated the development of bsADCs for solid tumors, including CRC. BsAbs and bsADCs provide opportunities to improve tumor selectivity, enhance internalization, overcome antigen escape, and expand the population of CRC patients eligible for targeted therapy. Emerging preclinical studies demonstrate encouraging anti-tumor activity for bispecific modalities in CRC, while early clinical trials are beginning to establish their translational potential. This review summarizes the current landscape of bsAbs and bsADCs in therapeutic development for CRC, highlighting key biological targets, engineering strategies, mechanisms of action, and clinical status. We also discuss the major challenges facing clinical translation and provide perspectives on future directions for bispecific therapies in CRC.

Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is a marker of cancer stem-like cells frequently upregulated in colorectal cancer (CRC) with lower expression in normal tissues, making it a favorable target for antibody-drug conjugates (ADCs). ADCs combine antibody specificity with potent cytotoxic payloads to enhance efficacy while minimizing systemic toxicity. LGR5-targeting ADCs incorporating different payloads demonstrate strong initial tumor inhibition, yet tumors eventually recur due in part to LGR5 downregulation, necessitating more effective strategies to prevent relapse. We show treatment with chemotherapies or an LGR5-targeting ADC coupled to a topoisomerase 1 inhibitor payload (8E11-CPT2) reduces LGR5 levels and increases MET receptor expression and/or activation in CRC cells, supporting a therapeutic approach to target LGR5 and MET simultaneously. Accordingly, we engineered a MET-targeting ADC (ABT-700-SG3199) via site-specific conjugation of the anti-MET antibody telisotuzumab (ABT-700) with the DNA-crosslinking pyrrolobenzodiazepine (PBD) dimer SG3199. ABT-700-SG3199 exhibited superior potency and efficacy in CRC models compared to the clinical-stage MET-targeting ADCs ABBV-399 and ABBV-400, which use the same antibody backbone conjugated to different payloads. Treatment with ABT-700-SG3199 increased LGR5 expression, and the combination of ABT-700-SG3199 with 8E11-CPT2 enhanced CRC cell-killing efficacy, reinforcing the rationale for a dual-targeting approach. In patient-derived xenografts, combined administration of 8E11-CPT2 and ABT-700-SG3199 markedly delayed tumor relapse and prolonged survival compared with single-agent treatment. Taken together, these findings reveal a reciprocal regulation between MET and LGR5 in response to LGR5- or MET-targeting ADCs in CRC models and support a LGR5/MET dual-targeting therapeutic strategy to enhance efficacy and potentially overcome resistance and relapse.