Improving treatment responses to solid tumours with trispecific TCEs

Following Zymeworks’ presentation at AACR 2024, in this Q&A, Dr Nina Weisser explains how the next generation trispecific T cell engager platform with integrated CD28 costimulation is engineered to tackle solid tumours.

T cell

What is the main advantage of TriTCE Co-Stim over conventional CD3-engaging bispecific T cell engagers (TCEs) in the treatment of solid tumours?

The development of conventional CD3-engaging bispecific TCEs for solid tumours has progressed slowly compared to TCE development for hematologic malignancies and demonstrated limited antitumour activity. These challenges are related in part to limited intratumoural T cell availability and poor T cell function (T cell anergy) commonly present in solid tumours. Additionally, as bispecific TCE activate T cells through Signal 1 (CD3) only, they have the potential to drive T cell responses to less functional (anergic or exhausted) states, thus further limiting the ability of bispecific TCE to drive durable antitumour responses. Zymeworks’ TriTCE Co-Stim is a next generation trispecific T cell engager platform with integrated CD28 “signal 2” costimulation. By providing balanced activation of both Signal 1 (CD3) and costimulatory Signal 2 (through CD28) within a single molecule, TriTCE Co-Stim molecules have the potential to induce more sustainable T-cell responses in the tumour and increase therapeutic responses beyond that achievable by bispecific TCEs. By enhancing T cell responses, TriTCE Co-Stim have the potential to increase the depth and durability of antitumour responses in patients with difficult to treat solid tumours with low T cell infiltration and poor T cell function, that are under-served by existing immune based therapies.

What is the key feature of the lead CLDN18.2 TriTCE Co-Stim molecule compared to comparator bispecific TCEs?

The lead CLDN18.2 TriTCE Co-stim molecule widens the therapeutic window in the treatment of Claudin18.2 expressing tumours with improved antitumour activity and good safety profiles. In the presence of tumour cells expressing CLDN18.2, the simultaneous engagement of CDLN18.2 on tumour cells with dual CD3/CD28 co-engagement on T-cells is anticipated to yield higher functioning T-cells capable of driving more durable T-cell responses, culminating in sustained antitumour activity. We tested this hypothesis in vitro in low effector to target cell and serial repeat challenge cytotoxicity assays, with results demonstrating superior T cell viability, T cell proliferation, and tumour cell cytotoxicity over time with the lead CLDN18.2xTriTCE molecule relative to clinical-stage benchmark traditional bispecific CLDN18.2 X CD3 T-cell engagers from Amgen (AMG 910) and Astellas (ASP2138). These results translated in vivo where TriTCE Costim mediated enhanced antitumour activity and intertumoural T cell infiltration and activation in established gastric cancer models.

How does the design of the TriTCE Co-Stim facilitate CD28 activation?

Various design features, such as modified paratope affinities and antibody formats, were optimised through protein engineering and reiterative functional screening to enable certain key functional properties desired in the platform. This includes conditional binding of CD28 contingent on CD3 binding, obligate cis T-cell binding of CD28 and CD3 with no T-cell cross linking between CD3 and CD28 on separate T-cells, and T-cell activation strictly contingent upon tumour antigen engagement.  

In comparison to comparator bispecific TCEs, what were the results of the TriTCE Co-Stim in humanised models of gastric cancer?

The lead CLDN18.2 TriTCE Co-Stim mediated superior antitumour activity compared to the CLDN18.2 X CD3 bispecific from Amgen (AMG910) in an established gastric cancer model humanised with naïve human effector cells (peripheral blood mononuclear cells, PBMC). This activity was accompanied with increased intratumoural T cell infiltration and activation, and reduced peripheral T cell expansion, compared to AMG910. These data corroborate the differentiating mechanistic in vitro data observed with TriTCE Co-stim compared to bispecific TCE, to elicit enhanced target dependent antitumour and T cells activity.

In non-human primates, how was the CLDN18.2 TriTCE Co-Stim tolerated upon repeat dosing?

In a pilot NHP study, the CLDN18.2 TriTCE Co-Stim molecule was well-tolerated upon repeat dosing at 3 mg/kg, with mild changes in peripheral cytokines and no histopathological changes observed in the stomach where CLDN18.2 is expressed.

What were the observed cytokine levels in human peripheral blood mononuclear cells when incubated with the CLDN18.2 TriTCE Co-Stim in the absence of tumour target engagement?

No detectable cytokine levels over negative control treatment were stimulated from human PBMCs when incubated with the CLDN18.2 TriTCE Co-Stim lead in the absence of tumour target engagement in vitro, as well as in an in vivo cytokine release mouse model humanised with human PBMC.

About the author

Nina Weisser, Director, Preclinical Multispecific Antibody Therapeutics at Zymeworks Inc.

Nina Weisser, PhD, is Director, Preclinical Multispecific Antibody Therapeutics at Zymeworks Inc. She has more than 20 years of experience in antibody biologics and has spent the past 12 years at Zymeworks focused on the development of multispecific therapeutics, including zanidatamab which she led from discovery to early development. Nina now leads the preclinical programs group and plays a key role in the development of the company’s lead clinical candidates and preclinical research programs. Dr Weisser received a PhD in Antibody Engineering from the University of Guelph.

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