Abstract 1017P
Background
KD033 is a clinical-stage bispecific fusion molecule consisting of a high-affinity anti-human-PD-L1 antibody and human IL-15. Previous preclinical studies with mouse anti-PD-L1/IL-15 (KD033 surrogate) have demonstrated that targeting IL-15 with anti-PD-L1 antibody resulted in increased efficacy, safety and maximal tolerated dose of the fusion protein compared to administrations of free IL-15. Reduction of tumor growth in both PD-L1 positive and negative tumor models was also observed. (Mol Cancer Ther, February 1 2021 (20) (2) 347-356) The goal of the current study is to evaluate the efficacy of KD033, the human anti-PD-L1/IL-15, in a human PD-1/PD-L1 transgenic mice, with human-PD-L1 positive and negative tumor cells.
Methods
KD033 was administered in the human-PD-L1/PD-1 transgenic C57/Bl6 mice subcutaneously transplanted with human(h)-PD-L1 positive and negative MC38 colon carcinoma cells. This animal model allowed the evaluation of human anti- PD-1 or PD-L1 agents. Furthermore, this model can be used to evaluate the efficacy of anti-PD-L1- targeting agents when PD-L1 is expressed in the animal but is either absent or present on the tumor cells.
Results
As was observed with KD033 surrogate, KD033 treatment resulted in significant tumor growth reduction in both h-PD-L1 positive and negative MC38 tumors. Analysis of peripheral immune cell populations showed similar increases in CD8 T and NK cells between h-PD-L1 positive and negative MC38- bearing mice after KD033 administration. Immunohistochemistry demonstrated an increase in CD8 T-cell infiltration into the h-PD-L1 positive MC38 tumors, whereas NK cells infiltration was more pronounced in the h-PD-L1 negative MC38 tumors. Analysis of tumor gene transcription after KD033 treatment highlighted differences in gene signatures between h-PD-L1 positive and negative MC38 tumors following KD033 treatment.
Conclusions
These results showed that the efficacy of anti-PD-L1-IL-15 fusion protein is not limited to PD-L1 tumor expression as KD033 was efficacious in both PD-L1 positive and negative tumors.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The study was done by Kadmon Corporation, LLC. Animal studies were conducted in WuxiAppTec Inc. with approved SOP and IACUC protocol. Nanostring platform analysis was done for Kadmon by Canopy Biosciences.
Funding
Kadmon Corporation, LLC.
Disclosure
S. Martomo: Financial Interests, Personal, Full or part-time Employment: Kadmon Corporation; Financial Interests, Personal, Stocks/Shares: Kadmon Corporation. D. Lu: Financial Interests, Personal, Full or part-time Employment: Kadmon Corporation; Financial Interests, Personal, Stocks/Shares: Kadmon Corporation. Z. Polonskaya: Financial Interests, Personal, Full or part-time Employment: Kadmon Corporation; Financial Interests, Personal, Stocks/Shares: Kadmon Corporation. X. Luna: Financial Interests, Personal, Full or part-time Employment: Kadmon Corporation; Financial Interests, Personal, Stocks/Shares: Kadmon Corporation. Z. Zhang: Financial Interests, Personal, Full or part-time Employment: Kadmon Corporation; Financial Interests, Personal, Stocks/Shares: Kadmon Corporation. G. Regev: Financial Interests, Personal, Full or part-time Employment: Kadmon Pharmaceutical; Financial Interests, Personal, Stocks/Shares: Kadmon Pharmaceutical. O. Schueller: Financial Interests, Personal, Full or part-time Employment: Kadmon Corporation; Financial Interests, Personal, Stocks/Shares: Kadmon Corporation. J. Patel: Financial Interests, Personal, Full or part-time Employment: Kadmon Corporation; Financial Interests, Personal, Stocks/Shares: Kadmon Corporation.