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TJ-CD4B Aims to Expand the Bispecific Antibody Portfolio as Phase 1 Trial Kicks Off

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I-Mab Biopharma and ABL Bio, Inc set their sights on adding the bispecific antibody, TJ-CD4B, to the expanding armamentarium for patients with various types of advanced and metastatic solid cancers.

I-Mab Biopharma and ABL Bio, Inc set their sights on adding the bispecific antibody, TJ-CD4B, to the expanding armamentarium for patients with various types of advanced and metastatic solid cancers. On March 30, 2021, the FDA approved the companies’ investigational new drug application allowing investigators to initiate the phase 1 dose-escalation trial of the investigational agent.1

TJ-CD4B, also known as ABL111, is being developed collaboratively by I-MabI, a global biotech company headquartered in Shanghai, China, focused on the discovery, development, and future commercialization of novel and highly differentiated biologics in the immuno-oncology therapeutic area, and ABL, a South Korean biotechnology company developing antibody therapeutics for immuno-oncology and neurodegenerative diseases. ABL has previously developed Grabody-T, a modular 4-1BB engaging platform.1

“TJ-CD4B is a bispecific antibody which engages with claudin 18.2 (CLDN18.2), an antigen expressed by cancer cells, and 4-1BB, a co-stimulatory molecule on immune cells, bringing them in close proximity,” explained Taylor Guo, PhD, the chief scientific officer of I-Mab, in an interview with OncLive®. “The binding of both antigens simultaneously to TJ-CD4B activates a cytotoxic immune response that is specifically directed against the cancer cells. The activated T-cells also produce memory T-cells that ‘remember’ the cancer antigens and launch an attack if it is encountered again in the future. Since the immune response is initiated only in the presence of the cancer antigen, it is directed only against the tumor cells with minimal damage to other cells of the body.”

According to findings presented at the American Association for Cancer Research Annual Meeting II in 2020, TJ-CD4B had a stronger binding capability to CLDN18.2 compared with IMAB362, a benchmark monoclonal antibody against CLDN18.2. The agent was also shown to have greater 4-1BB activity than the benchmark 4-1BB monoclonal antibody urelumab. Additionally, results showed that TJ-CD4B demonstrated strong tumor growth inhibition of CLDN18.2 expressing tumor cell in a humanized 4-1BB mouse model, while increasing tumor infiltrating lymphocytes with no impact on peripheral lymphocytes.2

“Monoclonal antibodies targeting 4-1BB alone have been ineffective as they cause generalized activation of immune system which also damages the healthy cells in the body resulting in systemic toxicity and liver damage,” Guo said. “With TJ-CD4B, the immune response is dependent on the presence of CLDN18.2 antigen, and is directed specifically against the cancer cells, thus minimizing the systemic toxicity. Preclinical studies have shown that the TJ-CD4B stimulates a stronger immune response than monoclonal antibodies directed against 4-1BB, even at low levels of CLDN18.2.”

The newly approved trial will be a multi-center, dose escalation study of TJ-CD4B in the United States. The primary end point include the safety, tolerability, pharmacokinetics, and pharmacodynamics of the agent in patients with advanced or metastatic solid tumors. Dose expansion studies of TJ-CD4B are also planned for later this year in China, examining patients with gastric cancers, gastro-esophageal junction adenocarcinoma, esophageal adenocarcinoma, and pancreatic ductal adenocarcinoma.1

“Guided by translational medicine research, we will explore [in the future] the treatment potentials [of TJ-CD4B] in the cancer types where there is high expression of CLDN18.2 and where there are

insufficient treatment options currently, such as gastric, esophageal, and pancreatic cancers,” Guo concluded.

References

  1. I-Mab and ABL Bio receive US FDA approval to initiate phase 1 trial of bispecific antibody TJ-CD4B/ABL111 in patients with advanced or metastatic solid tumors. I-Mab. March 30, 2021. Accessed April 20, 2021. https://www.i-mabbiopharma.com/en/article-623.aspx
  2. Jiang W, Fang Lm Wang Z, et al. Abstract 5644: claudin 18.2 X 4-1BB bispecific antibody induced potent tumor inhibition through tumor-specific 4-1BB activation. Cancer Res. 2020;80(suppl 16):5644. doi:10.1158/1538-7445.am2020-5644
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