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

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Effective T-cell responses require T-cell receptor (TCR) engagement (signal 1) and costimulatory signals (signal 2).
• T-cell bispecific antibodies (TCBs) like glofitamab provide signal 1 by engaging CD3ε and tumor antigens, demonstrating efficacy in CD20-expressing lymphomas.
• Enhancing T-cell costimulation may deepen and prolong T-cell-mediated tumor cell killing.

Purpose of the Study:

• To develop and evaluate a bispecific CD19-targeted CD28 agonist (CD19-CD28), RG6333, as a combination therapy to enhance TCB efficacy.
• To assess the safety and efficacy of RG6333 in combination with glofitamab for treating aggressive lymphomas.
• To investigate the potential of combining RG6333 with other costimulatory agonists.

Main Methods:

• Development of RG6333, a CD19-targeted CD28 agonist with engineered features for selective activity.
• Ex vivo assays using patient-derived peripheral blood mononuclear cells and spleen samples to evaluate T-cell effector functions.
• In vivo studies using humanized mice with aggressive lymphomas to assess tumor regression and long-term control.

Main Results:

• RG6333 enhanced T-cell effector functions in ex vivo assays when combined with glofitamab.
• The combination of glofitamab and RG6333 promoted regression of aggressive lymphomas in humanized mice.
• A triple combination including glofitamab, RG6333, and a 4-1BB agonist (CD19-4-1BBL) demonstrated superior long-term tumor control compared to dual combinations or glofitamab monotherapy.

Conclusions:

• RG6333 is a safe and effective combination partner for glofitamab and similar TCBs, enhancing T-cell mediated anti-tumor activity.
• The engineered CD19-CD28 agonist offers a promising strategy to improve outcomes in lymphoma treatment.
• RG6333 is currently under investigation in a Phase 1 clinical trial (NCT05219513) in combination with glofitamab.