NEW YORK – CDR-Life is aiming to overcome the challenges that come with developing and commercializing cell-based T-cell receptor therapies by advancing a pipeline of antibody-based T-cell engagers directed to promising cancer targets.
The Zurich, Switzerland-based biotech this week received clearance from the US Food and Drug Administration to launch a Phase I trial of its lead product candidate CDR404, a bispecific T-cell engager that targets melanoma-associated antigen 4 (MAGE-A4), a protein in the family of cancer/testis antigens that is expressed across a number of different cancers, including melanoma and non-small cell lung, head and neck, ovarian, urothelial, and gastroesophageal cancers. The trial will enroll patients based on MAGE-A4 expression and a human leukocyte antigen biomarker.
As part of the major histocompatibility complex (MHC), MAGE-A4 peptides are presented on the cell surface complexed with human leukocyte antigens. This enables T cells to recognize the difference between cells that are part of the body and foreign cells.
Because T cells already interact with the MHC, MAGE-A4 has emerged as an attractive target for T-cell receptor engineered T-cell (TCR-T) therapies like Adaptimmune's afamitresgene autoleucel, an autologous MAGE-A4-targeted cell therapy in development for synovial sarcoma, and 2seventy Bio and JW Therapeutics' MAGE-A4 TCR-T JWTCR001.
CDR-Life CEO Christian Leisner said the problem with the TCR-T approach is that "it's just been so incredibly difficult on the manufacturing side with these individualized therapies."
With bispecific T-cell engagers, though, manufacturing is much more straightforward, and there are other advantages, such as the ability to dose patients repeatedly, as opposed to a one-time autologous T-cell therapy treatment, he explained. Leisner also believes that the bispecific T-cell engager strategy may prove more powerful because it can recruit many different types of T cells to attack the tumor, rather than only relying on the engineered T cells.
Leisner acknowledged, however, that developing bispecific T-cell engagers for treating solid tumors, as opposed to hematological malignancies, does present some challenges. "You only have certain T cells in that tumor microenvironment," he said. "You may not have the same sort of flow of effector cells around the cancer cells as you do in hematology. You don't want to exhaust the T cells, but you also don't want to activate them too promiscuously."
Another consideration, Leisner noted, is that many traditional solid tumor targets are also expressed on normal cells to some extent, which can become a problem if the therapy is highly potent. Those considerations led the company to focus on MHC peptides as potential targets, since they are highly tumor specific, leading to the discovery of CDR404 as a therapeutic candidate.
CDR-Life's bispecific antibodies have a proprietary design that Leisner described as "two plus one," in that the antibody has two tumor cell binding regions and one region that binds to a T cell. In the case of CDR404, it has two identical binding regions for the MAGE-A4 target and one for CD3, a surface protein on T cells. The dual binding for MAGE-A4 is intended to increase the binding strength and potency of the drug.
Other companies developing T-cell engagers include Immunocore and Immatics. Immunocore markets Kimmtrak (tebentafusp-tebn), a bispecific T-cell engager targeting gp100, as a treatment for HLA-A*02:01-positive advanced uveal melanoma and is advancing a clinical pipeline of similar products in various cancer indications, though none are targeting MAGE-A4. Immatics is developing adoptive cell therapies and bispecific T-cell engagers in a variety of indications, and in May 2022, began a Phase I/II trial of the MAGE-A4- and MAGE-A8-targeted T-cell engager IMA401.
Leisner sees an advantage for CDR-Life's antibody-based products compared to these other programs, which are based on fusion proteins. "Antibodies are well understood. They're drug-like, they're easy to handle, they're modular in how we can assemble them, and they're producible," Leisner said.
CDR-Life has in vitro data showing that CDR404 kills tumor cells, and in xenograft models of non-small cell lung cancer, Leisner said researchers saw "full eradication" of tumors. In the trial slated to begin in the coming months in the US and in Europe, the company will enroll about 45 patients with solid tumors. The first part will be a dose-escalation study, and in the second part, investigators will focus on certain tumor types, increasing the number of patients in certain cohorts.
To enroll in the trial, patients must test positive for the HLA-A*02 (A-02) serotype, which can be done via a standard commercial test, and their tumors must have a certain level of MAGE-A4 expression confirmed via immunohistochemistry testing. CDR-Life has developed an IHC assay to use within the trial, but there are other ways to test for MAGE-A4, such as RNA, that could be developed into a commercially viable companion diagnostic.
CDR-Life raised $76 million in Series A financing in April 2022, which it is using to advance the MAGE-A4 program. CDR404, as the lead agent in this program, will remain internally funded, Leisner said, though the company may consider partnering to advance its other programs.
CDR-Life is developing other early-stage products that are similar to the MAGE-A4 product. One area of investigation for those products, Leisner said, are T-cell engagers designed for patients with HLA serotypes other than A-02, which represents only about 45 percent of patients. Leisner said the company's pipeline covers four different HLA subtypes. CDR-Life is also developing a BCMA-, CD3-, and PD-L1-targeted tri-specific T-cell engager, CDR101, as a therapy for multiple myeloma and is working with Boehringer Ingelheim on BI771716, a program focused on degenerative diseases. Boehringer Ingelheim and CDR-Life are studying BI771716 in a Phase I trial as a treatment for geographic atrophy, an advanced form of age-related macular degeneration.