CS5007的临床前疗效与安全性，一种搭载拓扑异构酶1抑制剂载荷的EGFR×HER3双靶向抗体药物偶联物

Background: EGFR and HER3, members of the ErbB receptor family, are key oncogenic drivers that are frequently co-overexpressed across a variety of human epithelial malignancies, Both EGFR and HER3 are clinically validated therapeutic targets for cancer therapies. Therefore, simultaneously targeting both EGFR and HER3 offers a promising strategy to overcome tumor heterogeneity and adaptive resistance commonly observed with single-target approaches. CS5007 is constructed with 1) functional EGFR&HER3 arm to tackle tumor heterogeneity; 2) hydrophilic beta-glucuronide linker (our proprietary CSL20 linker) to ensure that the ADC has a mAb-like PK profile, stability and tumor selective cleavage; 3) potent, well-tolerated and clinically validated topoisomerase 1 inhibitor exatecan (Exa) conjugated to the antibody with a drug-to-antibody ratio (DAR) of 4. Methods & Results: CS5007 demonstrated high-affinity binding (single digit nM) to EGFR/HER3 single- and double-positive tumor cells, comparable to its naked bispecific antibody and its parental antibodies. Western blot analysis of tumor cell lines revealed that naked bispecific antibody treatment led to strong inhibition of ligand-induced EGFR/HER3 downstream signaling, indicating effective blockade of proliferative pathways and induction of apoptosis. CS5007 induced rapid internalization and potent cell killing in tumor cell lines, demonstrating its potential to overcome tumor heterogeneity. It also showed superior in vitr o cytotoxicity over a bispecific control ADC (BL-B01D1 analog) and monospecific EGFR- or HER3-targeting ADCs in various tumor cell lines, including an osimertinib-resistant NSCLC model. A single treatment with 5 mg/kg CS5007 demonstrated robust, antigen-dependent antitumor activity across multiple xenograft (CDX) models, including EGFR+, HER3+, and dual-positive tumors. CS5007 showed strong tumor growth inhibitory ability comparable to or exceeding that of the anti-EGFR and anti-HER3 monospecific ADCs, as well as the bispecific control BL-B01D1. CS5007 exhibited a mAb-like PK profile in the rodent model. In vitro human, mouse, and cyno serum studies showed minimal payload release after 7 days, suggesting robust stability in circulation. CS5007 was well tolerated in cynomolgus monkeys at 30 mg/kg, with dose-dependent hematolymphoid and intestinal effects being its major toxicity findings, consistent with other EGFR targeting treatment. Cyno TK data further confirmed its excellent circulating stability. Conclusions: With demonstrated enhanced signaling inhibition, superior efficacy across multiple solid tumor models, and a favorable safety margin in preclinical studies, CS5007 is planned for an IND submission in early 2026 to support clinical development in advanced solid tumors.