Clasp marries genetics with immunology for safer T-cell engagers in $150M raise

2024-03-20

免疫疗法

Clasp Therapeutics was created in response to a question posed by scientific co-founder Bert Vogelstein: How can tumour-specific characteristics be leveraged for a powerful immune system attack, while also sparing healthy tissues?

The answer: T-cell engagers (TCEs) designed to lock onto a combined genetic-immune signature present only on cancer cells.

Vogelstein, a renowned cancer geneticist and researcher at Johns Hopkins, was uniquely able to come up with this solution because he has a foot in two disparate cancer research schools of thought, Clasp chief executive Robert Ross told FirstWord.

“The world of immuno-oncology and the world of precision oncology don't overlap very much,” Ross said. “Bert has this strong background in cancer genetics, and a cancer genetics background kind of puts you in the precision oncology bucket. Yet at the same time he is part of an immuno-oncology institute. So he's one of the few people who can really bridge the gap between precision oncology and immuno-oncology. And that's what's led to us targeting mutated oncogenes, a precision oncology approach, but leveraging the T-cell to go after them.”

Vogelstein founded Clasp along with fellow Johns Hopkins researcher Drew Pardoll, who helped create immunotherapy companies Amplimmune and Jounce Therapeutics.

The potential for a precision immuno-oncology (IO) therapy that avoids normal tissues – and the safety issues that have plagued development of TCEs for solid tumours – prompted a striking $150 million series A for Clasp led by Catalio Capital Management, Third Rock Ventures, and Novo Holdings.

The funds will bring the biotech’s TCEs to the clinic for solid tumours and provide enough runway to generate in-human data, Ross said. Other investors participating in the round include Vivo Capital, Cure Ventures, Blackbird BioVentures, Pictet Alternative Advisors, American Cancer Society Cancer Society’s Bright Edge and Alexandria Venture Investments.

Immuno-genetic combo

Clasp is taking advantage of the biology of human leukocyte antigens (HLAs) to target oncogenic proteins that are typically only expressed intracellularly.

HLAs sample the internal proteins in a cell and express fragments on the surface for T-cells to see, like “a waiter carrying a tray with food,” Ross explained. The “food” peptides are well-known cancer-driving mutations like p53, KRAS, or PI3K.

Clasp’s TCEs are proteins engineered to recognize the specific combination of “food” and “tray,” he added, to ensure that healthy tissues aren’t affected by the immune attack.

The company has scoured clinical and translational data from patients to confirm that certain HLA-mutated peptide combinations are expressed naturally in tumour cells – though they often occur in such low numbers that they don’t trigger a T-cell attack.

That’s why TCEs are the perfect modality to leverage against these combo targets, Ross said, because they can ramp up a naturally-occurring interaction to therapeutically effective levels – without being hampered by safety issues that occur when an IO target is also expressed on normal tissues.

Target advantages

This tact could avoid some of the shortcomings of TCEs, Ross said. Common IO targets such as CD19, CD20, and BCMA are expressed preferentially on cancer cells – but they’re not completely absent from healthy cells – making them too toxic to treat solid tumours.

Plus, cancers can downregulate expression of those proteins, whereas oncogenic drivers are “fundamental to the cancer,” he added, and can’t be removed. But because those mutations are expressed intracellularly, they can’t be targeted by an antibody – which brings Clasp full-circle to its reasoning for HLA-oncogene combination targeting.

Clasp plans to pursue a tumour-agnostic approach in the clinic for its engineered proteins, which are designed to be easier to manufacture and reproduce than currently approved TCEs.