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

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P991176
    CD19-CD28 Agonist