NEOK001（ABL206）：一种同类首创的 B7-H3xROR1 双特异性 ADC，显示出增强的疗效和良好的耐受性

NEOK001 (ABL206) is a bispecific antibody-drug conjugate (ADC) designed to overcome limitations of monospecific targeting of B7-H3 and ROR1. NEOK001 is a symmetric 2+2 bispecific ADC with a drug-antibody ratio (DAR) of 4, conjugated with SYNtecan E™, a linker-payload containing the topoisomerase I inhibitor exatecan. B7-H3 is a tumor-associated immune regulator which has been associated with poor prognosis and is overexpressed in multiple cancers as well as several normal tissues. ROR1 is an embryonic protein which is associated with poor prognosis in multiple cancers. ROR1 is upregulated in various solid and hematological cancer types and plays a role in cancer stem cells, epithelial-mesenchymal transition, and chemoresistance, but is restricted in its expression in normal adult tissues. By selectively targeting two distinct, co-expressed tumor associated antigens with minimal co-expression in normal tissue, NEOK001 leverages this co-expression to achieve enhanced efficacy while reducing normal tissue binding/toxicity. In vivo efficacy studies were performed in B7-H3 and ROR1 expressing cancer cell line-derived xenograft (CDX) or patient-derived xenograft (PDX) models. NEOK001 at 6-10mg/kg or monospecific ADCs at the equivalent molar doses were administered. Non-human primate toxicity was evaluated with NEOK001 administered in two doses (Days 1 and 22) at 30, 60 and 90 mg/kg. NEOK001 demonstrates enhanced in vitro cytotoxicity compared to ROR1 and B7-H3 monospecific ADCs. In vivo , NEOK001 demonstrates tumor growth inhibition in 81% (n=37) and regression in 54% of PDX models across multiple tumor types including SCLC (3/4), HNSCC (3/4), ovarian (4/5), NSCLC (3/5), prostate (2/5), TNBC (2/5) and sarcoma (2/5). NEOK001 demonstrates greater efficacy compared to monospecific ADCs such as zilovertamab vedotin (ROR1 ADC) and I-Dxd (B7-H3 ADC) in SCLC, ovarian and NSCLC xenograft models (P<0.01-0.001). In the repeat-dose GLP tox study in non-human primates, dose dependent payload class effects were observed, including minimal to mild reversible cytopenias and minimal to moderate reversible gastrointestinal toxicity observed at 30 and 60 mg/kg with an HNSTD of 60 mg/kg. NEOK001 is a first in class B7-H3xROR1 bispecific ADC, combining the broad expression of B7-H3 with the selective expression of ROR1 to enhance tumor-specific binding while reducing toxicity to normal tissue. Therefore, NEOK001 will be a promising therapeutic drug and will enter the clinic in early 2026.