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

Medientyp: E-Artikel

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

Beteiligte: Sam, Johannes; Hofer, Thomas; Kuettel, Christine; Claus, Christina; Thom, Jenny; Herter, Sylvia; Georges, Guy; Korfi, Koorosh; Lechmann, Martin; Eigenmann, Miro Julian; Marbach, Daniel; Jamois, Candice; Lechner, Katharina; Krishnan, Sreenath M; Gaillard, Brenda Chédyna; Marinho, Joana; Kronenberg, Sven; Kunz, Leo; Wilson, Sabine; Briner, Stefanie; Gebhardt, Samuel; Varol, Ahmet; Appelt, Birte; Nicolini, Valeria G.; [...]

Erschienen: American Society of Hematology, 2024

Sprache: Englisch

DOI: 10.1182/blood.2023023381

ISSN: 0006-4971; 1528-0020

Schlagwörter: Cell Biology ; Hematology ; Immunology ; Biochemistry

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Beschreibung: 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. While 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 (RG6333, CD19-CD28) 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, as 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 lymphoma patient-derived PBMC and spleen samples, 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.

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