693P - Preclinical activity of HLX43, a PD-L1-targeting ADC, in multiple PD-1/PD-L1 refractory/resistant models

Background

PD-1/PD-L1 monoclonal antibodies have revolutionised the landscape of cancer treatment. Nonetheless, some PD-L1+ patients do not respond to or become resistant to such therapy. The elevated expression of PD-L1 in tumours makes it an attractive target for ADC development, which could potentially alter the treatment for PD-1/PD-L1 inhibitor refractory/resistant (R/R) cancers.

Methods

HLX43 is a novel PD-L1-targeting ADC consisting of an engineered anti-PD-L1 humanised IgG1 antibody linked to a camptothecin-based toxin, with a drug to antibody ratio of 8. Our innovative linker-payload is activated preferentially in the tumour microenvironment, enabling its tumour-specific release of the toxin without needing internalisation of the ADC. Toxin release in PD-L1+ cancer cells is efficient and tumour-specific, minimizing damage to normal cells and reducing systemic toxicity from non-specific toxin release in periphery. HLX43 was examined in antigen binding, internalisation, and plasma stability assays; efficacy studies were performed in multiple CDX and PDX models.

Results

HLX43 has been shown to have similar affinity and internalisation rates as the parental antibody. It was stable in the plasma of rats and cynomolgus monkeys. In in vivo efficacy studies, HLX43 induced tumour regression in multiple PD-L+ CDX and PDX models, and was well tolerated across all dosing groups. Weekly administration of HLX43 8 mg/kg for three times significantly reduced tumours in the MDA-MB-231 model without causing weight loss. HLX43 exhibited superior anticancer efficacy compared to anti-PD-L1-GGFG-Dxd at equal doses in all models tested, including those with low PD-L1 levels, high heterogeneity, and non-responsiveness to PD-1/PD-L1 inhibitors. Preliminary toxicity assessments demonstrated good tolerability of HLX43 in rats and cynomolgus monkeys, with the maximum tolerated dose being 60 mg/kg in rats and 10 mg/kg in non-human primates. GLP toxicology studies will explore a higher dose at 20 mg/kg.

Conclusions

HLX43 showed promising efficacy and tolerability in preclinical assessments. It may offer a novel treatment for PD-1/PD-L1 inhibitor R/R cancers like NSCLC, HNSCC, ESCC, MEL, and OVC.

Clinical trial identification

Editorial acknowledgement

Shiqi Zhong of Shanghai Henlius Biotech, Inc.

Legal entity responsible for the study

Shanghai Henlius Biotech, Inc.

Funding

Shanghai Henlius Biotech, Inc.

Disclosure

Y. Shan, R. Liu, G. Song, H. Song, J. Jiang, C. Jia, Y. Chen, X. Yuan, Z. Hou, X. Wang, X. Hou, Y. Shen, C. Hu, H. Wei, Q. Wang, J. Zhu: Financial Interests, Personal, Full or part-time Employment: Shanghai Henlius Biotech, Inc.