I-Mab, a clinical-stage biopharmaceutical company, announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to TJ-CD4B (also known as ABL111), a novel Claudin 18.2 x 4-1BB bispecific antibody, for the treatment of gastric cancer, including cancer of the gastroesophageal junction. This designation highlights the potential of TJ-CD4B as a novel therapy for this aggressive cancer with poor prognosis.
TJ-CD4B is designed to target Claudin 18.2 (CLDN18.2)-expressing cancer cells while simultaneously activating T cells via the 4-1BB co-stimulatory molecule, leading to a tumor-killing effect. Preclinical studies suggest that TJ-CD4B exhibits superior anti-tumor activity compared to current CLDN18.2 antibodies and 4-1BB agonistic antibodies, with minimal 4-1BB related systemic toxicity.
Clinical Development
TJ-CD4B is currently undergoing phase 1 clinical trials (NCT04900818) in both the U.S. and China, involving patients with advanced solid tumors, including gastric cancer, gastroesophageal junction carcinoma, esophageal adenocarcinoma, and pancreatic ductal carcinoma. The ongoing dose-escalation study has shown that TJ-CD4B is safe and well-tolerated at doses up to 3 mg/kg weekly. I-Mab plans to further advance the study in biomarker-selected populations.
Significance of Orphan Drug Designation
The FDA grants Orphan Drug Designation to investigational drugs and biologics intended for the treatment of rare diseases affecting fewer than 200,000 people in the U.S. This designation provides several benefits to drug developers, including seven years of market exclusivity upon FDA approval, tax credits for qualified clinical trials, and exemption from FDA application fees.
Gastric Cancer Burden
Gastric cancer remains a significant global health challenge, ranking as the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. Due to its asymptomatic nature in early stages, it is often diagnosed in advanced stages, resulting in a poor prognosis. Current therapies for advanced refractory gastric cancer offer limited clinical benefits. In the U.S., approximately 26,000 individuals are diagnosed with gastric cancer annually, accounting for about 1.5% of all new cancer diagnoses.
Mechanism of Action
TJ-CD4B, also known as ABL111, is designed to bind to tumor cells expressing Claudin 18.2, such as gastric and pancreatic cancer cells, and stimulate intra-tumoral T cells through the 4-1BB arm. This activation is intended to occur specifically upon tumor engagement, minimizing systemic toxicity. The bispecific antibody is being developed under a collaboration between I-Mab and ABL Bio, a South Korean biotechnology company.
