LONDON – A breakthrough technology for generating fully human T-cell receptors (TCR) is set to deliver next-generation T-cell therapies for treating solid tumors, following the €66 million (US$78.3 million) series A funding of T-knife GmbH.

The company is owner of a transgenic mouse that, in the same way that Ig transgenic mice produce fully human antibodies, is capable of generating fully human TCRs. That allows for efficient, factory-like generation and selection of TCRs for any human tumor antigen.

It took Thomas Blankenstein, T-knife scientific co-founder, long years of breeding to get the entire human TCR alpha and beta gene loci established in the HuTCR mouse. When inoculated with human tumor antigens, the mouse immune system recognizes them as foreign, but the TCRs it generates are entirely human.

A seed round of €8 million raised after Berlin-based T-knife was spun out of the Max-Delbruck Center for Molecular Medicine in 2018 allowed the company to validate the platform and show the mouse is doing what it is supposed to.

Based on that work, T-knife has generated TCRs against more than 90 different tumor antigens, said Elisa Kieback, co-founder and CEO.

The TCRs raised in the HuTCR mouse do not go through negative thymic selection, the process by which the human body ensures the T cells it generates do not react against self-antigens. That means they are seen as foreign and naturally engage the tumor antigen at which they are targeted, without the need for any modifications.

“The novel thing we are bringing is we don’t have to artificially modify and affinity mature them; it’s all done in the mouse,” Kieback told BioWorld. T cells expressing its TCRs look at a tumor cell in the same way they would look at a pathogen, she said.

During the past two years, the company has built its expertise in tumor target selection and TCR sequence isolation and characterization.

“The mouse is basically a discovery tool: we identify the [TCR] sequence and then synthesize it,” Kieback said.

The mode of delivery will be similar to current CAR T therapies. “We will take T cells from the patient and introduce the sequence using a viral vector,” said Kieback.

Initially, T-knife is working on delivery of a single TCR, but it is planned to develop products delivering multiple TCRs in the future.

The first clinical trial, set up by the academic founders and publicly funded, has just started to recruit. The study, in multiple myeloma, is targeting melanoma-associated antigen 1 (MAGE1). The same product will also be T-knife’s lead program, with a trial in a number of different solid tumors due to start in 2021.

Kieback said the series A will be invested over three years. In addition to the MAGE1 targeted trial, a further three programs will enter the clinic in that time.

The latest round was led by heavyweight U.S. investors Versant Ventures and RA Capital Management, with the seed investors Andera Partners and Boehringer Ingelheim Venture Fund following on.

Olivier Litzka, partner at Andera, told BioWorld he was impressed by the utility of the technology and the huge amount of work that has gone into cloning the human TCR gene loci into the HuTCR mouse.

“It reminds me of the Medarex and Abgenix antibody platforms 15 years ago. Of antibodies on the market today, most go back to those platforms. Can we do a Medarex or an Abgenix with this [HuTCR] mouse?” said Litzka. There are grounds to believe the T-knife platform has equivalent capabilities, he said.

For Kieback, the size of the round and the transatlantic syndicate is an important validation. “We’ve found the perfect match of investors, who will help us in the future. They have networks and the right contacts in the industry,” said Kieback.

As a sign of their interest in the field, the day before the announcement of the T-knife series A, the two U.S. backers separately announced they are investing in two other T-cell startups. Versant is launching Matterhorn Biosciences to develop TCRs that recognize cancer-specific metabolites on the surface of tumor cells, while RA Capital is contributing to a $20 million seed round for Gentibio Inc., which is commercializing research in engineering T cells to induce immune tolerization in autoimmune, allergic and inflammatory diseases.

Kieback said having attracted U.S. investors will help T-knife to establish a U.S. presence, expand the management team, and begin to form external partnerships to out-license patented TCRs and/or the HuTCR mouse for de novo discovery.

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