Trispecific Antibodies Show Promise in Treating Cancer and Other Diseases

Large pharmaceutical companies are marking investments in the development of trispecific antibodies, which represent a new class of therapies. They are designed to target three different antigen-binding sites. No trispecific therapies have been approved, and research is still in its earliest phases with much of the research focused on cancer, inflammatory conditions and infectious diseases.

In a paper published last year in Theranostics, oncology researchers in Spain wrote about proof of concept studies that have shown that trispecific antibodies have the potential to overcome some of the obstacles of bispecific antibodies, including dosing and treatment resistance. But they also said there are important challenges for developing trispecifics that need to be overcome, including stability and manufacturing.

“From the perspective of healthcare costs, multispecific antibodies are appealing, since a similar (or superior) therapeutic effect could be obtained with a single therapeutic agent as with a combination of different monoclonal antibodies,” they wrote. “Despite challenges in production, multispecific antibodies are endowed with unprecedented properties, which may render them more potent biologics for cancer therapy.”

One pharmaceutical company investing in trispecific research in a big way is Merck. This year, Merck has acquired two companies focused on trispecific research, as well as invested in a separate research collaboration.

In the first deal, Merck acquired Harpoon Therapeutics in March 2024 for about $680 million. Harpoon’s lead candidate, MK-6070 (formerly known as HPN328), is a T-cell engager targeting delta-like ligand 3 (DLL3), a ligand that is expressed at high levels in small cell lung cancer (SCLC) and neuroendocrine tumors.

MK-6070 is currently being evaluated as monotherapy in a phase 1/2 clinical trial in certain patients with advanced cancers associated with expression of DLL3. The study is also evaluating MK-6070 in combination with atezolizumab in certain patients with small cell lung cancer.

Last month, Merck and Daiichi Sankyo teamed up to codevelop MK-6070 in combination with ifinatamab deruxtecan (I-DXd) in certain patients with small cell lung cancer, as well as other potential combinations.

“Small cell lung cancer is an aggressive, fast-growing form of lung cancer and new treatment approaches are urgently needed,” Dean Y. Li, M.D., Ph.D., president, Merck Research Laboratories, said in a news release. “We are pleased to build upon our collaboration with Daiichi Sankyo and look forward to evaluating the novel combination of MK-6070 and ifinatamab deruxtecan in small cell lung cancer and other forms of cancer.”

In the second deal, Merck acquired Eyebiotech in July 2024, whose lead candidate is Restoret (EYE103), for. $1.3 billion upfront and up to $1.7 billion in future milestone payments. Restoret is a potentially first-in-class tetravalent, trispecific antibody that acts as an agonist of the Wingless-related integration site (Wnt) signaling pathway.

Restoret is expected to begin a phase 2b/3 trial to treat patients with diabetic macular edema (DME) in the second half of 2024. Results from the open-label phase 1b/2a AMARONE study in patients with diabetic macular edema (DME) and neovascular age-related macular degeneration (NVAMD) showed that treatment with Restoret led to a mean improvement in best-corrected visual acuity of +11.2 letters and a mean reduction in retinal thickness measured by optical coherence tomography.

Another company investing in trispecific research is Gilead Sciences, which earlier this year signed an agreement with Merus to discover novel dual tumor-associated antigens (TAA) targeting trispecific antibodies. The companies will Merus’ proprietary Triclonics platform along with Gilead’s oncology expertise to research and develop multiple, separate preclinical research programs.

The agreement provides Merus with a $56 million upfront cash payment for initial targets, as well as an equity investment by Gilead of $25 million in Merus common shares. Merus is also eligible to receive up to $1.5 billion for development milestones.

Johnson & Johnson is another company conducting research and clinical trials of trispecific antibodies. The company is currently recruiting patients for a phase 1 trial of JNJ-80948543 in patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia. JNJ-80948543 is a T-cell engaging trispecific antibody that targets CD79b, CD20 and CD3.

Last year at the annual meeting of the American Society of Hematology, researchers presented data on the effect of a different therapy, J&J’s JNJ-79635322, in various myeloma cell lines in vitro. JNJ-79635322 is trispecific antibody composed of an anti-CD3 binding domain an anti-BCMA binding domain and an anti-GPRC5D binding domain. A phase 1 study is ongoing.