Authors:

Di Sun¹, Huanhuan Guo¹, Chaping Cheng³, Hongjun Li¹, Xinlai Yao¹, Shuang Lu¹, Jie Ding¹, Shenjie Zhang¹, Shijie Zhou¹, Jiamei Pan², Wei Tang², Steven Yu¹, Yi Gu¹, Xueming Qian¹

¹Suzhou Transcenta Therapeutics Co., Limited, Suzhou, China; 

²HJB (Hangzhou)Co., Limited, Hangzhou, China; 

³State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, and Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, China

Abstract:

Cancer associated fibroblast (CAF) is a rich source of factors for immune suppression and promotes cancer progression and metastasis via epithelial to mesenchymal transition (EMT). It is well known that tumors with mesenchymal phenotype have significantly poor prognosis and reduced response to checkpoint inhibitors. Targeting CAF becomes an increasingly attractive cancer therapeutic approach. Gremlin-1 is a member of the TGFβ superfamily, expressed by CAFs and tumor cells, and known to play a key role in EMT transition, cancer cell proliferation and stroma maintenance[1]. Gremlin-1 overexpression in CAF or tumor cells often correlates with poor clinical prognosis in multiple cancers including prostate, pancreatic, gastric cancer, lung cancer etc.

Here we describe the characterization of TST003, a novel humanized IgG1 monoclonal antibody targeting Gremlin-1. TST003 bound to human Gremlin-1 with high affinity and high selectivity, and blocked Gremlin-1 binding to BMP2/4 with an EC50 of 3.68 nM for BMP2 and 4.53 nM for BMP4 respectively. TST003 could dose-dependently reverse Gremlin-1 inhibition of the BMP4-mediated Smad1/5/9 phosphorylation in tumor cells as measured by western blot. In an ex vivo assay using prostate cancer patient-derived organoids (PDOs), TST003 inhibited the growth of 9 out of 12 human PDOs significantly. The in vivo activity of TST003 was evaluated using a human prostate cancer PC3 xenograft model on castrated male nude mice and a human colorectal cancer patient derived xenograft (PDX) mouse model in the presence of human PBMC. Both tumor models expressed Gremlin-1 as detected by IHC analysis. TST003 exhibited single agent tumor growth inhibition (TGI>50%) at 10 mg/kg. TST003 increased the infiltration of CD3/CD8 T cells into the tumor and the expression of PD-L1 in the CRC tumor. In addition, a significantly better anti-tumor activity was observed when TST003 combined with an anti-VEGFR2 antibody in the CRC PDX (MSS, Kras G12D, PD-L1 negative) model.

The safety profiles of TST003 were characterized in the single and repeated dose toxicology studies integrated with safety pharmacology, local tolerance, and in vitro hemolysis study, TCR study, and cytokine release study. TST003 was well tolerated in cynomolgus monkeys without noteworthy abnormalities following a single dose or repeated doses.

In summary, TST003 is a first-in-class therapeutic mAb targeting Gremlin-1 overexpressed by CAFs and tumor cells. Our preclinical characterization results provided the rationale for on-going clinical evaluation of TST003 in patients with advanced solid tumors with high unmet medical need either as monotherapy or in combination with SoC.

Conclusions:

•TST003, a humanized IgG1 anti-Gremlin-1 antibody, binds specifically to human Gremlin-1 with high affinity
•TST003 dose-dependently reversed Gremlin-1 mediated BMP signaling inhibition
•TST003 displayed anti-tumor activity either as single agent or in combination with standard of care in tumor models of prostate cancer and MSS colorectal cancer.
•TST003 could induce the infiltration of CD3 and CD8 T lymphocytes and increase PD-L1 expression in tumor
•TST003 displayed excellent tolerability and safety profiles in NHP in single and repeated dose toxicity studies following i.v. administration.
•These data warrants further evaluation of the clinical activity of TST003 either as single agent or in combination with other agents in patients with solid tumors.