Cancer immunotherapy comes in several forms, and one area of growing research interest is a type of drug called a T cell engager. These drugs bind to a cancer cell and a T cell simultaneously, bringing both of them together to spark a therapeutic effect. Robert Ross, CEO of Clasp Therapeutics, likens T cell engagers to the chaperone at a middle school dance who grabs a boy and a girl in each hand, getting them to dance together. But in cancer drugs, just as in school dances, sometimes the pairing just isn’t right.
The wrong pairing in cancer happens when a drug that’s targeted to a tumor also hits healthy cells, causing toxic effects. Clasp is developing a new kind of T cell engager designed to specifically target only cancer cells. The preclinical startup, which splits its operations between Cambridge, Massachusetts, and Rockville, Maryland, launched on Wednesday, revealing its science along with $150 million in financing.
The targeting ability of a T cell engager comes from its design: one antibody binds to a specific target on a cancer cell and another antibody binds to a target on a T cell. However, while the cancer targets addressed by these drugs are more abundant on cancer cells than healthy tissue, some amount is still found on healthy tissue. That limits how high a dose can be safely given to patients before the toxic effects become unacceptable. Ross said Clasp’s drugs won’t face that limitation.
“We are going after targets that are expressed on tumor tissue, but should not be expressed on normal tissue at all,” he said. “The beauty of that is you can dose up and up and up.”
Clasp isn’t disclosing it’s cancer targets just yet. But Ross said they are mutations that don’t exist in human bodies except in malignant tissue. Also, Clasp can go after targets that are inside of a cell. The targeting ability of the antibodies that comprise currently available T cell engagers can only address targets on a cell’s surface. Clasp’s approach leverages the human leukocyte antigen (HLA) system, which presents proteins on the surface of a cell to tell the immune system which cells belong to the body and which do not. Even when a tumor target is inside a cell, HLA still presents peptides from that target on the cellular surface. By going after that specific signature, Clasp’s drugs can hit intracellular tumor targets and avoid healthy tissue, Ross said.
One of the ongoing problems of cancer immunotherapy is patient selection. Clasp addresses that by designing a therapy to address a particular combination of a cancer-driving mutation and HLA type. It’s here where Clasp builds on existing clinical practice. HLA typing has been done for years as a way to match organs to transplant patients, Ross explained. There are tests for that. Those tests can also be used to understand if a patient has the right HLA type for a Clasp drug.
Clasp’s approach is not as personalized as a CAR T-therapy, which is made by engineering a patient’s own immune cells. But designing a drug for a particular HLA type offers what Ross calls a “spectrum of personalization,” a well-defined group of patients who have a particular cancer mutation and a specific allele. The scope of patients eligible for a Clasp drug will be smaller than that of say, a checkpoint inhibitor. But one problem with that type of immunotherapy is some patients don’t benefit and it’s not clear why. Going after a defined patient spectrum means there’s a much better sense of who will benefit and who will not, Ross said. He added that as someone who earlier in his career was a practicing oncologist, there’s also value in telling patients which treatments won’t work for them. But with Clasp’s technology, finding a therapy that will work is a matter of using the same scaffold to design a drug addressing a different cancer mutation and HLA type combination.
“I strongly believe in the power of immuno-oncology,” said Ross, whose experience includes senior roles at Bluebird Bio and Surface Oncology. “I also strongly believe we need to do a better job in selecting patients.”
The path for T cell engagers was blazed by Amgen’s Blincyto, whose 2014 FDA approval was the first in this class. But Blincyto only treats blood cancers and its label also carries a black box warning, a consequence of the drug picking up some healthy cells as dance partners. Biotech industry players are pursuing various approaches to safely bringing T cell engagers to solid tumors. Sanofi has acquired technology that “masks” a T cell engager, keeping it inactive and undetectable until it reaches its target. Takeda Pharmaceutical’s approach to a safer T cell engager employs drugs that activate only at the site of a tumor. Early-stage Janux Therapeutics employs a different technology to achieve tumor-specific activation. Others with research efforts in this drug class include Bristol Myers Squibb and Boehringer Ingelheim.
Clasp’s drugs are not antibodies. Ross describes them as “antibody-like” with manufacturability comparable to antibodies. The technology is based on about a decade of research in the Johns Hopkins University lab of Bert Vogelstein, a professor of oncology and pathology known for his discoveries in somatic mutations, mutations that are non-hereditary. Clasp formed in 2020, backed by seed financing from Catalio Capital Management and Third Rock Ventures, both of which had previously invested in cancer diagnostics startups founded by Vogelstein. Clasp took the research of Vogelstein and Johns Hopkins Professor of Oncology Drew Pardoll and ran with it. Ross joined the startup last November. After Clasp was able to reproduce the scientists’ work, Ross said it was time to bring the science to investors.
Clasp’s Series A financing was led by Catalio, Third Rock, and Novo Holdings. Other investors in the round include Vivo Capital, Cure Ventures, Blackbird BioVentures, Pictet Alternative Advisors, American Cancer Society’s Bright Edge and Alexandria Venture Investments. Ross said the size of the financing reflects the broader financial environment. Companies that raised money several years ago but haven’t yet reached the clinic are now finding they need to raise money again, but without any human data to show investors. Ross said Clasp’s financing should be enough to get the company to the point where it has the clinical data to get investors excited about another round. He declined to offer timelines for Clasp, but said reaching the clinic is the startup’s number one priority.
Ross pointed to companies in the T cell engager space that have recently reported encouraging clinical data that bolster the drug class. Amgen’s efforts to improve on T cell engagers include tarlatamb, now under FDA review after meeting the goals of its pivotal Phase 2 test in small cell lung cancer. Meanwhile, Janux’s recent report of positive interim Phase 1 data for its lead T cell engager enabled that biotech to raise capital through a stock offering.
“I see a rising tide here when it comes to T cell engagers and the potential benefits in solid tumors,” Ross said.
