Anti-Pd-L1/Il-15 Fusion Protein Generates Robust Adaptive Immune Gene Signatures In Tumours Leading To Tumour Inhibition And Memory Responses

Abstract Background We have generated a therapeutic anti-PD-L1/IL-15 fusion protein (KD033) by combining a proprietary, fully human, high affinity anti-PD-L1 antibody with human IL-15. We have also generated a surrogate KD033 by combining an anti-mouse PD-L1 surrogate antibody with human IL-15. Both KD033 and KD033 surrogate significantly increased CD8+ T, NK and NKT cells in peripheral blood in monkeys and mice respectively. KD033 surrogate treatment resulted in tumor clearance and generated memory responses in syngeneic mouse models of colon carcinoma. We examined the extent of memory responses in these KD033 surrogate-treated tumor-free mice and evaluated the molecular mechanisms of KD033 surrogate efficacy. Methods Mouse CT26 colon carcinoma cells were grown subcutaneously in Balb/c mice prior to intravenous treatments with fusion proteins. Tumor-free mice were re-challenged with tumors from the same genetic background. For immune gene expression analysis, tumors were isolated 7 days after treatments and analyzed using the mouse PanCancer IO 360 Gene Expression Panel from Nanostring. Results KD033 surrogate treatment was associated with increased cytotoxic lymphocyte infiltrations in tumors and the microenvironment. One hundred percent (100%) of KD033 surrogate-treated tumor-free animals rejected the same tumor without any additional treatments. Mice re-challenged with unrelated tumors from the same background were rejected or demonstrated reduction of tumor growth without further treatments. KD033 surrogate-treated tumors showed significant increases in expression of genes involved in cytokine, adaptive and inflammatory pathways and upregulation of immune gene signatures involving not only cytotoxic cells but also dendritic and B cells. Conclusions KD033 surrogate inhibited tumor growth inhibition and demonstrated evidence of epitope spreading. Broad activation of innate and adaptive immune responses in tumors was observed. These observations strongly support KD033 clinical development. A phase I clinical trial of KD033 is planned in 2H 2019. Legal entity responsible for the study Animal studies were conducted for Kadmon by Crown Bioscience Inc. with approved SOP and IACUC protocol. Nanostring platform analysis was done for Kadmon by Canopy Biosciences. Funding Kadmon Corporation, LLC. Disclosure S. Martomo: Full / Part-time employment: Kadmon Corporation. X. Feng: Full / Part-time employment: Kadmon Corporation. D. Lu: Full / Part-time employment: Kadmon Corporation. Z. Polonskaya: Full / Part-time employment: Kadmon Corporation. X. Luna: Full / Part-time employment: Kadmon Corporation. M.V. Poyurovsky: Full / Part-time employment: Kadmon Corporation. K. McCracken: Full / Part-time employment: Kadmon Corporation. F. Miyara: Full / Part-time employment: Kadmon Corporation. L. Li: Full / Part-time employment: Kadmon Corporation. S. Aggarwal: Full / Part-time employment: Kadmon Corporation. J. Patel: Full / Part-time employment: Kadmon Corporation.