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Bivalent CD47 Immunotoxin for Targeted Therapy of Lung Cancer
Abstract:
Lung cancer is the leading cause of cancer-related deaths in the world, with ∼2.5 million people diagnosed and ∼1.5 million deaths each year. While the last two decades have yielded substantial progress with systemic targeted and immune therapies improving treatment responses in subgroups of patients with advanced and refractory lung cancer, there is still a dire unmet clinical need to develop more effective therapies with durable responses. CD47 receptors are overexpressed on the surface of a variety of malignant tumor cells including lung cancer. Although there has been increasing interest in developing targeting antibodies against CD47 for immunotherapy, they failed clinical trials due to their dose-limiting toxicities, primarily hematopoietic toxicity. Using a unique diphtheria toxin resistant Pichia pastoris yeast expression system, we have developed a diphtheria toxin-based bivalent CD47 immunotoxin (bi-CD47-IT) for targeted therapy of CD47 + non-small cell lung cancer (NSCLC). Bi-CD47-IT demonstrated compelling preclinical efficacy in multiple NSCLC cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models, including subcutaneous, orthotopic, metastatic and humanized models. This study demonstrates the remarkable preclinical activity of bi-CD47-IT against various lung cancer models, making bi-CD47-IT a novel and promising therapeutic approach for NSCLC.
Insights
A novel diphtheria toxin-based immunotoxin targeting CD47 receptors shows promise for treating non-small cell lung cancer (NSCLC). This therapy, bi-CD47-IT, demonstrated significant preclinical efficacy in various lung cancer models.
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.
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