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Fully human anti-mesothelin CAR with low immunogenicity for in vivo persistence of anti-tumor engineered T cells

Description:

The fully human CAR targets mesothelin, a surface protein overexpressed in several cancer types. P4, a human antibody fragment that binds human mesothelin with high specificity, is fused to T cell signaling domains such as 28z. The T cells engineered to express this CAR are shown to shrink tumors in a mouse model bearing human ovarian tumors overexpressing mesothelin. 

 

Problem: 

Though engineered anti-mesothelin chimeric antigen receptor (CAR) T cells show encouraging pre-clinical results against certain cancer types, their clinical efficiency is stunted by their poor long-term persistence in infused human patients.

 

Indeed, anti-mesothelin CARs are generally designed using mouse antibody fragments, which can trigger a detrimental immune response against the CAR T cells and destroy them (Maus et al, 2014), thus limiting their cancer destroying potential to a narrow time-frame. 

 

Solution: 

Instead of using a mouse antibody fragment for engineering CARs, Dr. Powell and his team have produced a fully human anti-mesothelin CAR that shows high cancer killing potential, yet very low immunogenicity.

 

 

Human ovarian tumor regression in an immunodeficient mouse model. Top panels: Mice infused with fully human anti-mesothelin (P4-28z) CAR T cells show significant regression of ovarian tumor (in color) between day 12 (day of infusion) and day 29. Bottom panels: Mice infused with negative control CD19-28z CAR T cells show ovarian tumor progression (Lanitis et al, 2012). 

 

Application: 

Therapy efficient against mesothelin-expressing tumor cells.

 

Advantages: 

  • In vivo persistence of infused CAR T cells after infusion.
  • Low immunogenicity compared to mouse-derived antibody fragments.
  • Not inhibited by soluble mesothelin secreted by cancer cells.

 

Stage of Development: 

  • Target identified
  • Preclinical discovery

 

Intellectual Property: 

US20140301993

 

Reference Media: 

Lanitis et al, Mol Ther. 2012 Mar; 20(3): 633–643. 

 

Desired Partnerships: 

  • License
  • Co-development

 

Docket # Y6105


Patent Information:
For Information, Contact:
Robert Hormann
University of Pennsylvania
rhormann@upenn.edu
Inventors:
Daniel Powell
Keywords:
Antibody
Autoimmune
Immunology
Immunotherapy
Oncology