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

  • Blood. 2024 May 23;143(21):2152-2165. doi: 10.1182/blood.2023023381.
Johannes Sam  1 ,  Thomas Hofer  1 ,  Christine Kuettel  1 ,  Christina Claus  1 ,  Jenny Thom  1 ,  Sylvia Herter  1 ,  Guy Georges  2 ,  Koorosh Korfi  1 ,  Martin Lechmann  2 ,  Miro Julian Eigenmann  3 ,  Daniel Marbach  3 ,  Candice Jamois  3 ,  Katharina Lechner  2 ,  Sreenath M Krishnan  3 ,  Brenda Gaillard  1 ,  Joana Marinho  1 ,  Sven Kronenberg  3 ,  Leo Kunz  1 ,  Sabine Wilson  4 ,  Stefanie Briner  1 ,  Samuel Gebhardt  1 ,  Ahmet Varol  1 ,  Birte Appelt  1 ,  Valeria Nicolini  1 ,  Dario Speziale  1 ,  Miriam Bez  1 ,  Esther Bommer  1 ,  Jan Eckmann  2 ,  Carina Hage  2 ,  Florian Limani  1 ,  Silvia Jenni  1 ,  Anne Schoenle  1 ,  Marine Le Clech  1 ,  Jean-Baptiste Pierre Vallier  1 ,  Sara Colombetti  1 ,  Marina Bacac  1 ,  Stephan Gasser  1 ,  Christian Klein  1 ,  Pablo Umaña  1
Affiliations
  • 1. Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland.
  • 2. Roche Innovation Center Munich, Roche Pharma Research and Early Development, Penzberg, Germany.
  • 3. Roche Innovation Center Basel, Roche Pharma Research and Early Development, Basel, Switzerland.
  • 4. Roche Innovation Center Welwyn, Roche Pharma Research and Early Development, Welwyn Garden City, United Kingdom.
PMID: 38437725 DOI: 10.1182/blood.2023023381
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.

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