45P - Therapeutic potential of ISM8207: A novel QPCTL inhibitor, in triple-negative breast cancer and B-cell non-Hodgkin lymphoma

Background

Glutaminyl-peptide cyclotransferase-like protein (QPCTL), mediates the trafficking of monocytes as well as the CD47/SIRPa interaction which blocks macrophage phagocytosis. Genetic deletion of QPCTL in tumor or host immune cells promotes anti-tumor activity. We evaluated ISM8207, a novel QPCTL inhibitor, in preclinical triple-negative breast cancer (TNBC) and B-cell Non-Hodgkin Lymphoma (B-NHL) models.

Methods

Gene expression datasets, METABRIC (TNBC), and GSE4475 and GSE10846 (diffuse large B cell lymphoma [DLBCL]), were analyzed for association between QPCTL expression and overall survival (OS). In vitro SIRPα binding to the human cell lines (MDA-MB-231, TNBC; and Raji, B-NHL) was evaluated after pre-treatment with ISM8207. In vivo antitumor efficacy was assessed in the murine 4T1 TNBC model and in human B-NHL OCI-Ly10 or Raji xenografts in CB17 SCID mice treated with ISM8207.

Results

Patient tumor dataset analyses revealed QPCTL was overexpressed in TNBC and DLBCL, and that a higher expression correlated with a shorter OS. ISM8207 treatment (IC50 < 0.5 nM in enzymatic assay) phenocopied the genetic deletion of QPCTL and reduced the binding of SIRPα to CD47 in TNBC cells, without affecting cell viability. In the murine 4T1 TNBC model, ISM8207 (30 mg/kg BID) demonstrated modest but significant anti-tumor activity. Circulating monocytes and the binding affinity of SIRPα to peripheral white blood cells were reduced. ISM8207 combined with an anti-PD-1 antibody potently and synergistically inhibited tumor growth, with Tumor Growth Inhibition (TGI) of ∼50%. The bulk RNA-seq profiling for combined ISM8207 and anti-PD-1-treated tumors showed a higher infiltrating potential of CD8⁺ T-cells in the tumor microenvironment vs anti-PD-1 alone. ISM8207 (10 mg/kg BID) combined with rituximab resulted in synergistic effects in the B-NHL xenografts. In the Raji model, TGI with the combination was 86% vs 41% with rituximab alone. In the OCI-Ly10 model, 7/8 mice achieved complete remission with the combination vs 1/8 with rituximab alone. ISM8207 was well-tolerated with favorable ADME and PK properties.

Conclusions

These data strongly support the clinical evaluation of ISM8207 as a novel cancer immunotherapy in TNBC and B-NHL.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Shanghai Fosun Pharmaceutical Development Co. LTD and Insilico Medicine.

Disclosure

S. Rao, Y. Fu, M. Zhang, L. Qin, S. Bavadekar, H. Cui, C. Xu, S. Chen, F. Ren: Financial Interests, Personal, Full or part-time Employment: Insilico Medicine. C. Yang, S. Yan, X. Wang: Financial Interests, Personal, Full or part-time Employment: Shanghai Fosun. X. Xiang, L. Liu, L. Diao: Financial Interests, Personal, Full or part-time Employment: Beijing Fosun.