Conditional PD-1/PD-L1 Probody Therapeutics Induce Comparable Antitumor Immunity but Reduced Systemic Toxicity...

Area of Science:

• Oncology
• Immunology
• Biotechnology

Background:

• Immune-checkpoint blockade revolutionized cancer therapy but often requires combination treatments, increasing toxicity.
• Systemic T-cell activation from combination therapies leads to both enhanced efficacy and adverse effects.
• Protease-activatable antibody prodrugs (Pb-Tx) offer localized antibody activity within the tumor microenvironment.

Purpose of the Study:

• To evaluate the efficacy and safety of Probody therapeutics (Pb-Tx) targeting PD-L1 and PD-1.
• To assess if localized inhibition of PD-1/PD-L1 by Pb-Tx can elicit antitumor immunity with reduced systemic toxicity.

Main Methods:

• Systemic administration of anti-PD-L1 and anti-PD-1 Pb-Tx in tumor-bearing mice.
• Evaluation of antitumor activity compared to traditional antibodies.
• Assessment of systemic activity, peripheral T-cell target occupancy, and autoimmune side effects in nonobese diabetic mice.

Main Results:

• Pb-Tx demonstrated antitumor activity comparable to traditional PD-1/PD-L1 antibodies.
• Pb-Tx exhibited reduced systemic activity and an improved nonclinical safety profile.
• Markedly reduced target occupancy on peripheral T cells and decreased incidence of autoimmune diabetes were observed.

Conclusions:

• Localized PD-1/PD-L1 inhibition via Pb-Tx effectively elicits antitumor immunity.
• Pb-Tx minimizes systemic immune-mediated toxicity, offering a safer therapeutic approach.
• These findings support the clinical development of anti-PD-L1 Pb-Tx CX-072.