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Optimized synthetic consensus inmunogenic compositions targeting fibroblast activation protein

A technology of immunogenicity and immunogenic fragments, applied in the field of immunogenic compositions, can solve problems such as lethal toxicity and slowing down of tumor progression by T cells

Pending Publication Date: 2019-08-23
THE WISTAR INST OF ANATOMY & BIOLOGY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The groups additionally showed that T cells expressing chimeric antigen receptors targeting FAP slowed tumor progression; however, in some mouse strains, these CARs caused lethal toxicity

Method used

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  • Optimized synthetic consensus inmunogenic compositions targeting fibroblast activation protein
  • Optimized synthetic consensus inmunogenic compositions targeting fibroblast activation protein
  • Optimized synthetic consensus inmunogenic compositions targeting fibroblast activation protein

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0244] Example 1: Synthetic Consensus FAP Immunogenic Compositions

[0245] The FAP protein is a protease and gelatinase expressed on activated fibroblasts. FAP is expressed in >90% of cancer-associated fibroblasts in human cancers, including in prostate and pancreatic cancers. FAP is also expressed in fibroblasts involved in wound healing and in malignant cells of bone and soft tissue sarcomas. Antibodies against FAP (eg, sibulizumab) and small molecule inhibitors of FAP (eg, talabostat) are safe but have shown minimal efficacy in clinical trials.

[0246] Over the past decade, there has been a surge of interest in developing immunotherapies targeting FAP-expressing cells (Fang et al., 2016, Mol Ther Oncolytics, 3:16007; Gottschalk et al., 2013, PLoS One, 8:e82658; Zhang and Ertl, 2016, Oncotarget, 7:23282–99; Xia et al., 2016, Cancer Immunol Immunother, 65:613–624; Wen et al., 2010, Cancer Sci, 101:2325–2332; Xia et al., 2016, 34 :4526-4535; Chen et al., 2015, Sci Rep, ...

Embodiment 2

[0297] Example 2: Immunogenic Fragments of FAP

[0298] To characterize the response of mouse strains to native FAP peptides and to determine dominant epitopes, 122 peptides representing different epitopes of FAP were generated for the optimized consensus FAP (Figure 14A). When cells were stimulated with each pool, there were multiple responses (Figure 14B and Figure 14C), leading to the conclusion that there is not one dominant epitope but multiple subdominant epitopes ( Figure 15 ). Several subdominant epitopes (e.g., SEQ ID NO:22, SEQ ID NO:23, and SEQ ID NO:24) contained mutations in the optimized consensus FAP relative to native FAP ( Figure 15 ).

Embodiment 3

[0299] Example 3: Sequence Information

[0300]

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Abstract

Provided herein is an immunogenic composition comprising a synthetic consensus FAP antigen. Also disclosed herein is a method of treating or preventing a tumor associated pathology in a subject in need thereof, by administering the immunogenic composition to the subject.

Description

[0001] Cross References to Related Applications [0002] This application is entitled to priority to US Provisional Application No. 62 / 397,469, filed September 21, 2016, which is hereby incorporated by reference in its entirety. [0003] Statement Regarding Federally Sponsored Research or Development [0004] This invention was made with government support under Grant Nos. P50 CA 174523, U19 AI109646, and F32 CA213795 awarded by the National Institutes of Health and Grant No. W31P4Q-15- Conducted under 1-0003. The government has certain rights in this invention. technical field [0005] The present invention relates to immunogenic compositions targeting fibroblast activation proteins and methods of administering said immunogenic compositions. Background technique [0006] Solid tumor pathophysiology is characterized by an abnormal microenvironment that directs tumor progression and constitutes an obstacle to the efficacy of cancer therapies. Several proteins are overexpr...

Claims

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Application Information

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IPC IPC(8): A61K38/00A61K39/00A61P35/00A61P37/04C07K14/47C12N15/12
CPCA61K38/00C12Y304/21026C12N9/6424C07K2319/02A61P37/04A61P35/00A61K39/0011A61K2039/53A61K2039/54A61K39/001158A61K2039/70A61K39/001193A61K39/001157
Inventor 大卫·韦纳伊丽莎白·迪佩雷
Owner THE WISTAR INST OF ANATOMY & BIOLOGY
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