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Basic science

1548 - FPA150, a Novel B7-H4 Therapeutic Antibody with Checkpoint Blockade and ADCC Activities

Date

10 Sep 2017

Session

Basic science

Presenters

Charles Kaplan

Citation

Annals of Oncology (2017) 28 (suppl_5): v1-v21. 10.1093/annonc/mdx361

Authors

C.D. Kaplan1, D. Houser1, F. Kemp2, N. Nielson3, A. Hsu4, K. Legris5, G. Brattich6, H. Xiang7, A. Ahene4, U. Jeffry8, D. Bellovin2, L. Borges1

Author affiliations

  • 1 Immuno-oncology Research, Five Prime Therapeutics, 94080 - San Francisco/US
  • 2 Pharmacology, Five Prime Therapeutics, 94080 - San Francisco/US
  • 3 Flow Cytometry, Adimab, 03766 - Lebanon/US
  • 4 Bioanalytics, Five Prime Therapeutics, 94080 - San Francisco/US
  • 5 Molecular Biology, Five Prime Therapeutics, 94080 - San Francisco/US
  • 6 Protein Chemistry, Five Prime Therapeutics, 94080 - San Francisco/US
  • 7 Clinical Pharmacology, Five Prime Therapeutics, 94080 - San Francisco/US
  • 8 Toxicology, Five Prime Therapeutics, 94080 - San Francisco/US
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Resources

Abstract 1548

Background

B7-H4, a member of the B7 family of immune modulators, negatively regulates both T cell immune responses and anti-tumor immunity. While B7-H4 is highly expressed in a range of solid tumors, expression in heathy tissues is limited. Hence, we sought to generate a therapeutic antibody that both blocks the T cell inhibitory checkpoint activity of B7-H4 and mediates potent antibody-dependent cell-mediated cytotoxicity (ADCC) against B7-H4-expressing tumor cells.

Methods

Fully human B7-H4 antibodies raised by screening Adimab’s yeast-based platform were evaluated for protein and cell binding, epitope specificity, and species cross-reactivity. We assessed these B7-H4 antibodies for checkpoint blockade activity using our proprietary in vitro assay, comprised of primary human T cells and B7-H4-expressing artificial antigen presenting cells. We used primary human cell-based and reporter cell line-based assays to assess the in vitro ADCC activity of B7-H4 antibodies against B7-H4-expressing target cell lines. We assessed the in vivo anti-tumor efficacy of our lead B7-H4 antibody in mice bearing syngeneic tumor cell lines engineered to display mouse B7-H4.

Results

After generating a panel of B7-H4 antibodies, we found that 12 out of 41 antibodies reverse B7-H4-mediated inhibition of T cell proliferation and IFNg production in vitro. Importantly, 11 of these antibodies with checkpoint blockade activity belong to the same epitope bin, recognize the B7-H4 IgV domain, and fully cross-react with cynomolgus monkey and rodent B7-H4, suggesting that these antibodies bind and block an evolutionarily conserved functional domain. When glycoengineered for enhanced FcgRIIIa binding, selected checkpoint blockade antibodies also mediate potent ADCC activity against cells exhibiting a range of B7-H4 expression. In a murine tumor model expressing B7-H4, our selected therapeutic candidate FPA150 significantly impairs tumor growth in a dose-dependent manner.

Conclusions

We generated a therapeutic candidate B7-H4 antibody, FPA150, which possesses both T cell immune checkpoint blockade and ADCC activity. We initiated IND-enabling studies and plan to file an IND application by the end of 2017.

Clinical trial identification

Legal entity responsible for the study

Five Prime Therapeutics

Funding

Five Prime Therapeutics

Disclosure

C.D. Kaplan: Currently employed by and own stock in Five Prime Therapeutics. D. Houser, A. Hsu, K. Legris, G. Brattich, H. Xiang, A. Ahene, U. Jeffry, D. Bellovin, L. Borges, F. Kemp: Currently employed by Five Prime Therapeutics N. Nielson: Currently employed by Adimab.

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