CD19-CD28: an affinity-optimized CD28 agonist for combination with glofitamab (CD20-TCB) as off-the-shelf immunotherapy.

Autor:	Sam J; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Hofer T; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Kuettel C; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Claus C; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Thom J; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Herter S; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Georges G; Roche Innovation Center Munich, Roche Pharma Research and Early Development, Penzberg, Germany., Korfi K; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Lechmann M; Roche Innovation Center Munich, Roche Pharma Research and Early Development, Penzberg, Germany., Eigenmann MJ; Roche Innovation Center Basel, Roche Pharma Research and Early Development, Basel, Switzerland., Marbach D; Roche Innovation Center Basel, Roche Pharma Research and Early Development, Basel, Switzerland., Jamois C; Roche Innovation Center Basel, Roche Pharma Research and Early Development, Basel, Switzerland., Lechner K; Roche Innovation Center Munich, Roche Pharma Research and Early Development, Penzberg, Germany., Krishnan SM; Roche Innovation Center Basel, Roche Pharma Research and Early Development, Basel, Switzerland., Gaillard B; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Marinho J; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Kronenberg S; Roche Innovation Center Basel, Roche Pharma Research and Early Development, Basel, Switzerland., Kunz L; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Wilson S; Roche Innovation Center Welwyn, Roche Pharma Research and Early Development, Welwyn Garden City, United Kingdom., Briner S; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Gebhardt S; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Varol A; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Appelt B; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Nicolini V; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Speziale D; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Bez M; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Bommer E; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Eckmann J; Roche Innovation Center Munich, Roche Pharma Research and Early Development, Penzberg, Germany., Hage C; Roche Innovation Center Munich, Roche Pharma Research and Early Development, Penzberg, Germany., Limani F; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Jenni S; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Schoenle A; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Le Clech M; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Vallier JP; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Colombetti S; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Bacac M; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Gasser S; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Klein C; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland., Umaña P; Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2024 May 23; Vol. 143 (21), pp. 2152-2165.
DOI:	10.1182/blood.2023023381
Abstrakt:	Abstract: Effective T-cell responses not only require the engagement of T-cell receptors (TCRs; "signal 1"), but also the availability of costimulatory signals ("signal 2"). T-cell bispecific antibodies (TCBs) deliver a robust signal 1 by engaging the TCR signaling component CD3ε, while simultaneously binding to tumor antigens. The CD20-TCB glofitamab redirects T cells to CD20-expressing malignant B cells. Although glofitamab exhibits strong single-agent efficacy, adding costimulatory signaling may enhance the depth and durability of T-cell-mediated tumor cell killing. We developed a bispecific CD19-targeted CD28 agonist (CD19-CD28), RG6333, to enhance the efficacy of glofitamab and similar TCBs by delivering signal 2 to tumor-infiltrating T cells. CD19-CD28 distinguishes itself from the superagonistic antibody TGN1412, because its activity requires the simultaneous presence of a TCR signal and CD19 target binding. This is achieved through its engineered format incorporating a mutated Fc region with abolished FcγR and C1q binding, CD28 monovalency, and a moderate CD28 binding affinity. In combination with glofitamab, CD19-CD28 strongly increased T-cell effector functions in ex vivo assays using peripheral blood mononuclear cells and spleen samples derived from patients with lymphoma and enhanced glofitamab-mediated regression of aggressive lymphomas in humanized mice. Notably, the triple combination of glofitamab with CD19-CD28 with the costimulatory 4-1BB agonist, CD19-4-1BBL, offered substantially improved long-term tumor control over glofitamab monotherapy and respective duplet combinations. Our findings highlight CD19-CD28 as a safe and highly efficacious off-the-shelf combination partner for glofitamab, similar TCBs, and other costimulatory agonists. CD19-CD28 is currently in a phase 1 clinical trial in combination with glofitamab. This trial was registered at www.clinicaltrials.gov as #NCT05219513. (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
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