Authors:

Yelena Janjigian¹, Weijing Sun² ,Caio Max Sao Pedro Rocha Lima³,Satish Shah⁴, Aaron Scott⁵, Monga Dulabh⁶, Madappa Kundranda⁷, Amna Sher⁸, Philip Gold⁹, Jordan Berlin¹⁰, Manish R. Patel¹¹, Alese Olatunji¹², Erika Hamilton¹³, Michael Cecchini¹⁴, Brian Van Tine¹⁵, Ben George¹⁶, Rutika Mehta¹⁷, Simon Xia¹⁸ , Caroline Germa¹⁸, Nashat Gabrial ¹⁹

1. Memorial Sloan Kettering Cancer Center; 

2. University of Kansas Cancer Center;  

3. Comprehensive Cancer Center of Atrium Health Wake Forest Baptist; 

4. Pennsylvania Cancer Specialists and Research Institute, 

5. University of Arizona Cancer Center 

6. Drexel University School of Medicine AHN Cancer Institute, 

7. Banner MD Anderson, 

8. Stony Brook Cancer Center, 

9. Swedish Cancer Institute,
10. Vanderbilt-Ingram Cancer Center 

11. Florida Cancer Specialists and Research Institute, 

12. Winship Cancer Institute at Emory University, 

13. Sarah Cannon Research Institute, 

14. Yale Cancer Center

15. Barnes and Jewish Hospital Washington University St. Louis16. Medical College of Wisconsin, 

16. Medical College of Wisconsin, 

17. H. Lee Moffitt Cancer Center, 

18. Suzhou Transcenta Therapeutics 

19. Gabrial Cancer Center Research

Background:

• Gastric cancer (GC) remained the 4th leading cause of cancer death worldwide, accounting for about 7.7% of all cancer related mortality.

• Combinations of platinum and fluoropyrimidine are the preferred first-line chemotherapy regimen for patients with HER2 negative advanced gastric cancer. Nivolumab was approved in combination with chemotherapy for first-line treatment of patients with advanced or metastatic gastric cancer. Though treatment outcome being improved, the median overall survival of nivolumab plus chemotherapy was still less than 14 months.

• Claudin-18 isoform 2 (CLDN18.2) is a member of the human claudin family of tetraspan membrane proteins that are crucial structural and functional components of tight junctions. CLDN18.2 expression is strictly limited to differentiated epithelial cells of gastric mucosa. CLDN18.2 is ectopically expressed at a significant level in multiple tumor types including gastric, esophageal, pancreatic and lung cancers, making it an attractive anti-cancer target. In G/GEJ cancer, its expression is independent from PD-L1.

• Zolbetuximab (IMAB362) is a clinical stage anti-CLDN18.2 antibody, significant improvement in PFS and OS was demonstrated when zolbetuximab was added to mFOLFOX6 or to CapOX as compared to placebo plus mFOLFOX6 or CapOx. Results were limited to patients with CLDN 18.2 high expression (75%, 2+), which is about 38% of the population.

Preclinical Data:

• TST001 is a humanized IgG1 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) activity via reduced fucosylation, and has stronger anti-tumor activities than IMAB362 analog, a chimeric anti-Claudin 18.2 antibody. 

• TST001 has shown a more potent complement mediated cytotoxicity (CDC) and antibodydependent cellular phagocytosis (ADCP) activities against CLDN18.2 expressing cells than IMAB362 analog. , may up regulate PDL1 expression.
  In vivo studies in mouse syngeneic tumor models demonstrated better efficacy of TST001 in low CLDN 18.2 expressors vs IMAB362 analog. 

• The anti-tumor efficacy of triple combination of TST001 plus anti-PD-1 antibody and chemotherapy was significantly better than anti-PD-1 antibody in combination with chemotherapy or TST001 in combination with chemotherapy. 

Trial Status:

As of Apr 20, 2023, part A has been completed; part B is ongoing.