Authors:

Fei Teng¹, Huanhuan Guo¹, Hongjun Li¹, Lizhi Qin¹, Xinlai Yao¹, Lei Shi¹, Edward Drower¹, Yi Gu¹, Xueming Qian¹.

1. Suzhou Transcenta Therapeutics Co., Ltd, Suzhou, China

Background:

Fibroblast growth factor receptor 2 IIIb (FGFR2b), one of the four FGFR family members that encode transmembrane receptor tyrosine kinases, is overexpressed in a variety ocancers, such as gastric/GEJ (29%)¹, esophageal (41%)², squamous NSCLC (31%)³, TNBC (13%)³, ovarian (40%)³, endometrial (86%)⁴, cervical (80%)⁴, colorectal (62%)⁵, and cholangiocarcinoma (22%)³. We have developed a FGFR2btargeting ADC (TST105) with a novel topoisomerase I inhibitor payload by using glycotransferase mediated site-specific conjugation. Significant internalization, specific killing activity and bystander killing effect were observed in vitro. TST105 also shows outstanding in vivo tumor killing efficacy in gastric and colorectal tumor models, which may be contributed by the site-specific conjugation. These promising preclinical data support further investigations of TST105 in FGFR2b positive solid tumors.

Conclusions:

1. TST105 is a novel and potent FGFR2b-targeted monoclonal antibody 38D4 conjugated to a novel topoisomerase I inhibitor by using glycol based site-specific conjugation technology.

2. As 38D4 specifically binds to FGFR2b and can be internalized into FGFR2b expressing tumor cells, TST105 could induce specific cytotoxicity to these tumor cells with a potency between 0.3 nM and 0.4 nM in vitro.

3. TST105 expresses higher potent bystander effect than MMAE based ADCs.

4. TST105 produced a greater in vivo anti-tumor efficacy (SNU16) than Bema-MMAE (TGI: 91.25% vs 48.32%, ORR: 70% vs 0%).

5. TST105 produced a greater in vivo tumor inhibition effect (SW480-FGFR2b-medium) than 38D4-MMAE (TGI: 57.43% vs 1.92%).

6. TST105 is one of several potent, next-generation therapeutic agents under development targeting FGFR2b expression insolid tumors.