Costimulatory bispecifics bring new biology to T cell engagers
BY LAUREN MARTZ, EXECUTIVE DIRECTOR, BIOPHARMA INTELLIGENCE
Two T cell engaging bispecific antibodies may be better than one when it comes to driving activation of T cells against tumors, according to an emerging trend across two of the fall’s major conferences: the American Society of Hematology and Society for Immunotherapy of Cancer.
In abstracts released ahead of the two conferences, at least seven companies describe costimulatory bispecific or trispecific antibodies that, when paired with traditional CD3- targeting bispecifics, may drive a stronger T cell response. The idea of combining multiple bispecific T cell engagers isn’t new. Companies are pairing bispecifics against different tumor antigens in late-stage trials to address tumor heterogeneity and prevent resistance.
However, the costimulatory engager idea is different. It involves pairing bispecifics that bind the same tumor antigen but different targets on T cells — the idea is to engage two pathways that are now understood to be required for T cell activation. T cell activation happens when the T cell receptor (TCR) on the surface encounters an antigen presented by MHC molecules on an antigen presenting cell. Traditional bispecific T cell engagers target this activation mechanism by binding CD3, the signaling component of the T cell receptor complex.
The problem is that a second activation signal is also required for T cell activation, and that pathway isn’t always engaged on T cells, especially in immune suppressed environments.
In this type of dual bispecific approach, the TCR/CD3 signal is called signal 1 and a second “costimulatory” signal is called signal 2. The costimulatory signal happens when CD28, CD2 or another costimulatory receptor on T cells is engaged, often by a different ligand on antigen presenting cells or other immune cells.
While costimulatory bispecifics aren’t expected to have meaningful monotherapy activity, the hope is that combining a traditional bispecific that engages CD3 (signal 1) with a costimulatory bispecific (signal 2) will amplify the effects of the traditional compound.
Several pharmas and biotechs working in the T cell engager space are exploring costimulatory engagers. At ASH 2023, Roche (SIX:ROG; OTCQX:RHHBY) will present preclinical data on a CD28 x CD19 engager in hematological malignancies. Xencor Inc. (NASDAQ:XNCR) and IGM Biosciences Inc. (NASDAQ:IGMS) are also developing CD28- targeting bispecifics.
EvolveImmune Therapeutics Inc., a company launched in 2020, is developing bispecifics that target CD2, an alternative costimulatory receptor on T cells. Although CD28 is often considered the primary costimulatory receptor, EvolveImmune previously presented data showing that expression of CD28 and 4-1BB, another commonly targeted costimulatory receptor, was low or lost in tumor-infiltrating T cells, while CD2 expression was retained. That suggests CD2 could be a good drug target for driving costimulation in exhausted T cells. At SITC, the company presented preclinical data on two programs, including one against the novel tumor antigen ULBP2.
Other pharmas, including Novartis AG (SIX: NOVN; NYSE:NVS) and Sanofi (Euronext:SAN; NASDAQ:SNY), are developing multispecifics that hit T cell activation signals 1 and 2 through a single compound. These trispecific molecules typically target both CD3 and a costimulatory receptor on T cells, plus a tumor antigen.
Novartis has a CD2 x CD3 x CD19 trispecific in Phase I, according to an abstract released ahead of ASH, while Sanofi describes the CD28 x CD3 x CD38 trispecific SAR442257 in three separate ASH abstracts.
Zymeworks Inc. (NASDAQ:ZYME) is applying the trispecific concept to gastric cancer antigen CLDN18.2, with a compound that also targets CD28 and CD3.
Other companies working on costimulatory bispecifics not represented at the conferences include Regeneron Pharmaceuticals Inc. (NASDAQ:REGN). The company has four costimulatory bispecifics in Phase I development.
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