IDE034，一种共同靶向PTK7和B7-H3的双特异性抗体偶联药物，表现出亲合力驱动的选择性以及优于单特异性ADC的增强抗肿瘤活性

IDE034 is a humanized IgG1 bispecific antibody-drug conjugate (bsADC) that co-targets protein tyrosine kinase 7 (PTK7) and B7-homolog 3 (B7-H3), two tumor-associated antigens broadly expressed across refractory solid tumors but largely absent from normal tissues. Dual-antigen engagement by IDE034 is designed to enhance tumor cell-specific binding, avidity-driven internalization, and intracellular payload release relative to monospecific ADCs, thereby maximizing tumor payload exposure while minimizing normal tissue uptake. IDE034 binds human and cynomolgus PTK7 and B7-H3 with sub-nanomolar affinity and shows no cross-reactivity with other B7-family members. In dual-antigen-positive tumor cells, IDE034 exhibits saturable co-binding and superior internalization kinetics compared with B7-H3- or PTK7-monospecific ADCs. Target-dependent intracellular release of its topoisomerase I inhibitor (TOP1i) payload induces S-phase enrichment, G₂/M arrest, and apoptosis, with bystander cytotoxicity . In-vivo , IDE034 produced rapid and durable tumor regressions across PTK7/B7-H3 co-expressing xenograft models and consistently outperformed monospecific comparators. Because poly(ADP-ribose) glycohydrolase (PARG) is essential for resolving TOP1-DNA cleavage complexes, its inhibition has emerged as a strategy to amplify TOP1i-induced DNA damage. The clinical-stage PARG inhibitor IDE161 enhances accumulation of TOP1-DNA crosslinks and replication stress, resulting in deep and durable responses when combined with TOP1 inhibition. The combination of IDE034 with IDE161 reproduced the enhanced antitumor activity observed with TOP1 inhibitors, demonstrating that blockade of PARG-dependent DNA repair can maximize the therapeutic benefit of bispecific TOP1i-ADC-mediated DNA damage. By coupling dual-antigen recognition with a cleavable, membrane-permeable TOP1i payload, IDE034 has the potential to broaden the therapeutic window and address intratumoral heterogeneity. Given the reported frequency of detection of B7H3 and PTK7 protein expression across numerous tumor samples, double positive disease is anticipated to be prevalent in colorectal, non-small cell lung, and breast cancers. Together, these findings support IDE034 as a potential first-in-class bispecific TOP1i-ADC with broad opportunity across disease indications as a monotherapy and in combination with IDE161.