Conditionally Active CD28xVISTA Bispecific Antibodies Promote Myeloid-Driven T-cell Activation

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Bispecific antibodies (bsAbs) targeting CD28 offer a promising strategy for reinvigorating tumor-reactive T cells.
• Conditional, tumor-specific recruitment of T cells can improve therapeutic control and specificity.
• The acidic tumor microenvironment presents a challenge and an opportunity for targeted therapies.

Purpose of the Study:

• To develop pH-selective CD28xVISTA bsAbs for targeted T cell activation within the tumor microenvironment.
• To enhance T cell-mediated cancer cell killing while minimizing systemic T cell activation and cytokine release syndrome.
• To evaluate the efficacy and safety of these novel bsAbs in preclinical models.

Main Methods:

• Engineered pH-selective CD28xVISTA bsAbs with V-domain Ig components.
• Assessed pH-dependent VISTA engagement and CD28 signaling in reporter cell lines.
• Evaluated T cell activation, expansion, and cancer cell killing in vitro.
• Tested in vivo efficacy in a humanized CD28 syngeneic mouse model with MC38 tumors.
• Assessed cytokine release syndrome in vitro assays.

Main Results:

• The lead CD28xVISTA bsAb candidate demonstrated pH-dependent VISTA engagement and VISTA-dependent CD28 signaling.
• In vitro studies showed T cell activation, expansion, and enhanced cancer cell killing.
• The bsAb efficiently inhibited tumor growth in combination with PD-1 blockade in a humanized mouse model.
• No signs of superagonistic properties or significant cytokine release syndrome were observed in vitro.

Conclusions:

• pH-selective CD28xVISTA bsAbs can effectively target the tumor microenvironment for enhanced cancer immunotherapy.
• These bsAbs promote T cell activation and cancer cell killing with a favorable safety profile.
• The findings support the clinical development of CD28xVISTA bsAbs for solid tumors, potentially combined with anti-PD-1 or anti-CD3 therapies.