Bivalent CD47 Immunotoxin for Targeted Therapy of Lung Cancer

Area of Science:

• Oncology
• Immunotherapy
• Molecular Biology

Background:

• Lung cancer remains a leading cause of cancer mortality globally, with a significant need for improved therapies.
• While targeted and immune therapies have advanced lung cancer treatment, durable responses remain a challenge for advanced and refractory cases.
• CD47 receptor overexpression on lung cancer cells presents a therapeutic target, but CD47-targeting antibodies have faced toxicity issues in clinical trials.

Purpose of the Study:

• To develop a novel diphtheria toxin-based bivalent CD47 immunotoxin (bi-CD47-IT) for targeted therapy of CD47-positive non-small cell lung cancer (NSCLC).
• To evaluate the preclinical efficacy and safety of bi-CD47-IT in various NSCLC mouse models.

Main Methods:

• Utilized a unique diphtheria toxin resistant Pichia pastoris yeast expression system to create the bi-CD47-IT.
• Tested bi-CD47-IT in multiple NSCLC cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models, including subcutaneous, orthotopic, metastatic, and humanized models.

Main Results:

• Bi-CD47-IT demonstrated compelling preclinical efficacy across diverse NSCLC models.
• The immunotoxin showed significant anti-tumor activity in models representing various stages and types of lung cancer progression.

Conclusions:

• Bi-CD47-IT represents a novel and promising therapeutic approach for non-small cell lung cancer.
• The diphtheria toxin-based immunotoxin overcomes limitations of previous CD47-targeting strategies, offering potential for durable responses in NSCLC patients.