HONG KONG – Shanghai-based I-Mab Biopharma Co. Ltd. expects to begin clinical trials for the world’s first and only claudin18.2 and 4-1BB bispecific program in a year.

“We expect the trial to start in U.S. in the [middle of] next year. We will then expand the trial to China afterwards as planned,” Joan Shen, CEO of I-Mab, told BioWorld.

The candidate, TJ-CD4B, also known as ABL-111, was jointly developed with South Korea-based ABL Bio Inc. Under the cost-sharing collaboration agreement, I-Mab is leading the development of TJ-CD4B in mainland China, Hong Kong, Macau and Taiwan, while ABL Bio is responsible for South Korea.

“Outside the territories, the two companies establish a royalty and other incomes-sharing agreement if both decide to out-license a product candidate, where configurations depend on the final candidate,” said Shen.

TJ-CD4B is being developed initially for gastric and potentially pancreatic cancers since claudin18.2 is specifically expressed in those tumors, which have very few therapies available. The candidate is designed to enhance T-cell activation in a CLDN18.2-dependent manner. Thus, the presence of claudin18.2 and its expression level is critical to the efficacy of TJ-CD4B.

“While the human body is able to use the immune system to fight cancer cells, many cancers are able to evade detection and so escape destruction by the immune cells. When TJ-CD4B binds to claudin18.2 on the surface of a cancer cell and to 4-1BB on a T cell, it brings these two cells into close physical proximity. The T cell is then able to detect the tumor cell, gets fully activated and attack the tumor cell,” said Shen.

“Moreover, some of these T cells become long-lived and can remember and eliminate the tumor cells during the next encounter.”

There are three other claudin antibody-based approaches being developed, apart from bispecific antibodies: antibody-drug conjugates, antibody-dependent cellular cytotoxicity therapies and CAR T therapies.

Compared with those three modalities, I-Mab claims its bispecific antibody therapy offers multiple advantages.

“It is able to utilize two or more mechanisms to attack the cancer cells. It is designed to supercharge efficacy while at the same time reduce toxicity and it generates memory cells that generate a durable antitumor response,” said Shen.

She said she believes I-Mab’s bispecific antibody could potentially treat a wider range of patients, including those with tumors that have only a low level of claudin18.2 expression.

“Unlike earlier generations of 4-1BB antibodies that raised safety concerns, our bispecific antibody binds to a unique region on 4-1BB that activates it in a specific manner, enabling it to work safely and optimally as part of the T-cell machinery,” said Shen.

I-Mab had presented preclinical data on its asset at the American Association for Cancer Research Virtual Annual Meeting II in June.

“In preclinical studies, we found that TJ-CD4B can recognize cells expressing a wide range of claudin18.2 and activate T cells concurrently. Moreover, in a preclinical mouse model, TJ-CD4B/ABL-111 demonstrated strong tumor inhibition. The GLP tox study is ongoing,” said Shen.

The preclinical findings demonstrated a possibility of high, durable efficacy at lower doses and with greater tolerability in animal models. The company is now conducting IND-enabling studies with the goal of entering phase I trials in 2021 in the U.S.

Making clinical progress

It’s been an eventful year for I-Mab, starting with its $104 million IPO on Nasdaq. The company also has made progress in developing almost all of its clinical-stage assets.

The first is TJC-4, a highly differentiated CD47 monoclonal antibody that received an IND approval from the U.S. FDA in January 2019.

“We are at the final stage of the dose-escalation study with the highest dose level,” Shen said. “As the clinical data accumulate, we are now more confident about its key advantages. We have started a clinical trial in patients with AML in China. Our aim is to quickly advance to a pivotal trial after an accelerated dose/safety study.”

In May, the company also shared interim results from a clinical study on TJM-2, an I-Mab-discovered neutralizing antibody against human GM-CSF.

“Our clinical trial in patients with cytokines release syndrome (CRS) associated with severe COVID-19 is ongoing in the U.S. The study adopts a double-blind clinical trial design and aims to confirm clinical efficacy and safety of TJM-2 in the treatment of CRS associated with severe COVID-19,” said Shen.

“The first part of the study was completed successfully. We are now in the second part of study and the top-line data are expected in the third quarter of this year.”

Another update to the pipeline was for TJ-107, a novel long-acting recombinant human interleukin-7 (rhIL-7) it shares with Genexine Inc.

“We received regulatory clearance to start a phase II clinical trial in patients with glioblastoma multiforme (GBM) in China. This study design should allow us to measure potential early efficacy signal in response to increased T-cell count by the investigational drug and further evaluate the safety profile of this compound in treating GBM patients,” said Shen.

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