HONG KONG – I-Mab Biopharma (Shanghai) Co. Ltd. has received IND approval from China's National Medical Products Administration (NMPA) for its CD73 antibody, getting the go-ahead for a phase I/II trial of TJD-5 in patients with advanced solid tumors.

Joan Shen, head of R&D at I-Mab, told BioWorld Asia that TJD-5 has the potential to become a best-in-class immuno-oncology drug in combination with PD-1 or PD-L1.

"The clinical trial filed with the NMPA is a phase I/II dose-escalation study and a cohort expansion study of TJD5 monotherapy or TJD5 in combination with toripalimab in patients with advanced or metastatic cancers. This comes after the phase I [first-in-human] study in the U.S.," said Shen.

The study objectives include safety and tolerability, finding the maximum tolerated dose, determining recommended phase II dosages and evaluating pharmacokinetic and pharmacodynamic characteristics and preliminary efficacy. Objective response rate will be the preliminary endpoint, Shen said.

"TJD-5 is still at the early clinical development stage. Multiple indications, including non-small-cell lung cancer, will be evaluated based on the mechanism of actions, biomarker study results and other advanced scientific data," Shen added.

Guangdong Provincial General Hospital has been selected as the leading site for TJD-5 development in China. Other potential sites are under evaluation.

According to the company, CD73 is a target affecting tumor microenvironment. I-Mab's TJD-5 is among the first few anti-CD73 monoclonal antibodies in clinical development globally. I-Mab said it believes TJD-5 to be the first to obtain IND approval in China.

"The way TJD-5 binds to and inhibits CD73 is particularly interesting," Shen said. "By changing the amino acids in CD73 one at a time, we have been able to determine where TJD-5 binds to CD73.

"Results show that, unlike some other CD73 antibodies out there that bind to the N-terminal domain, TJD-5 binds to key residues in the C-terminal domain situated at the outside edge of the CD73 dimer interaction surface – we call this a unique epitope."

Different binding modes have different consequences. I-Mab said the intradimer binding mode results in complete CD73 inhibition, a more favorable pharmacological profile than other CD73 antibodies that act through an interdimer mode, which may cause what's known as the "hook effect," meaning that the inhibition is gradually lost at higher concentration of the drug – i.e. more isn't better – leaving a narrow therapeutic range to work with.

However, TJD-5 is still in very early clinical development. Shen cautioned it is difficult to be precise about the date of a potential BLA filling. "However, we will try our best to find an innovative way to pursue either conditional approval or accelerated approval based on the data and our negotiations with the NMPA. The earliest BLA submission date would be at or after 2024," she said.

In late November 2018, I-Mab and Tracon Pharmaceuticals Inc. announced a strategic partnership that covered TJD-5. They dosed the first patient in the U.S. for their phase I trial in August 2019.

In early April, I-Mab and Roche Holding AG reached a clinical supply agreement for TJD-5 phase I trials in the U.S.

I-Mab will keep the rights to the drug in the China market but intends to seek global partnerships for markets outside China once meaningful data are generated. A similar strategy will apply to the rest of its global portfolio.

Growing clinical pipeline

TJD-5 is the second in-house-developed innovative immuno-oncology compound moving to clinical development stage. I-Mab's China portfolio "today comprises five investigational drugs that are either in, or ready to enter, phase II and III clinical trials in greater China," Jielun Zhu, chief financial officer at I-Mab, told BioWorld Asia.

"The most advanced investigational drug, the anti-CD38 MAb TJ-202, is being evaluated in two product-registration trials for [relapsing/remitting] multiple myeloma – one assessing TJ-202 as a monotherapy, and the other as a second-line treatment with lenalidomide as a backbone treatment," Zhu said.

TJ-202, originally developed by Germany-based Morphosys AG, has demonstrated comparable efficacy and a better safety and tolerability profile in comparison with daratumumab.

I-Mab also recently in-licensed enoblituzumab, a humanized antibody directed at B7-H3, from U.S.-based Macrogenics Inc. As the only conventional B7-H3 antibody in clinical development worldwide, enoblituzumab has the potential to be a first-in-class immunotherapy for a variety of solid tumors that overexpress B7-H3.

I-Mab also has TJC-4, a fully human monoclonal antibody targeting CD47.

"TJC-4 is being evaluated in a phase I clinical trial in patients with cancers in the U.S., and no anemia has been observed in the first cohort of patients so far," said Zhu. "It had also received IND approval from China's NMPA in July 2019."

Indications for both solid tumor and hematological tumors will be explored by either monotherapy or combination therapy.

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