1265P - A promising MET-EGFR bispecific nanobody-drug conjugate therapy for multiple solid tumours

Background

MET and EGFR are classical tumor drive genes and highly co-expressed in multiple solid tumors. MET amplification is also associated with EGFR tyrosine kinase inhibitors resistance. These points demonstrated the rationale for MET and EGFR bispecific combination to enhance the therapeutic efficacy. KY-0301 is an ADC with a bispecific nanobody targeting MET and EGFR. When internalized, KY-0301 releases monomethyl auristatin E (MMAE) warhead that traps tubulin, inhibiting cell division by blocking the polymerization of tubulin.

Methods

The ADC was constructed on the backbone of TPEBEN (Tumor Penetration Enhancement by Engineered Nanobody) bispecific ADC platform. Several strategies were used for improving tumor therapy efficacy and safety. KY-0301 was engineered with lower EGFR affinity (161-fold) and EGFR arm truncation, with the aim of reducing EGFR-driven toxicity in normal tissues.

Results

KY-0301 showed higher internalization rates than AZD9592 in HCT116 and NCI-H1975. KY-0301 and AZD9592-MMAE showed high and similar cytotoxicity in vitro in 9 cancer cells with different antigens expression level, including EBC-1, HCC827, NCI-H1975, HT29, HCT116, 786-O, A498, BXPC-3 and ASPC-1. In vivo in cell-derived xenograft (CDX) models, KY-0301 showed a 95%-100% tumor growth inhibition (TGI) in EBC-1, NCI-H1975, HCT116 and HT29 at 2 mg/kg-4 mg/kg. KY-0301 showed better TGI than AZD9592-Dxd in EBC-1 CDX model at the same drug dose. KY-0301 monotherapy in vivo in patient-derived xenograft(PDX)models showed a 98% TGI in NSCLC tumor at 3 mg/kg and a 100% TGI in pancreatic tumor at 2 mg/kg. For safety evaluation with normal cells, KY-0301 showed weaker killing activity than AZD9592-MMAE with HFL-1, MIHA, BEAS-2B and MRC-5. No significant changes in body weight were observed in the Rhesus Macaque at the dose of 6 mg/kg. KY-0301 has also demonstrated outstanding molecular developability in Chemistry, Manufacturing, and Controls (CMC) with the expression titer of 8.5 g/L, final bispecific antibody yield of 6.0 g/L and DAR4 ADC purity of 98%.

Conclusions

Preclinical data has demonstrated promising efficacy and safety of KY-0301 in tumors expressing MET and EGFR, including but not limited to NSCLC, colorectal cancer, pancreatic cancer and kidney cancer.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Novatim Immune Therapeutics (Zhejiang) Co., Ltd.

Funding

Novatim Immune Therapeutics (Zhejiang) Co., Ltd.

Disclosure

X. Cai: Financial Interests, Personal and Institutional, Funding: Novatim Immune Therapeutics (Zhejiang) Co., Ltd. G. Wu: Financial Interests, Personal and Institutional, Ownership Interest: Novatim Immune Therapeutics (Zhejiang) Co., Ltd. C. Zhang, H. Yu: Financial Interests, Personal and Institutional, Full or part-time Employment: Novatim Immune Therapeutics (Zhejiang) Co., Ltd. All other authors have declared no conflicts of interest.