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Immunology

Abstract 2476: Bispecific redirected T-cell immunotherapy targeting P-cadherin expressing tumors

Timothy S. Fisher, Adam Root, Bryan Peano, Allison Rohner, Justin Lucas, Mark Elliott, Konstantinos Tsaparikos, Hui Wang, Jonathan Golas, Maria Gavriil, Susan Benard, Tao He, Tracey Clark, Nahor Haddish-Berhane, Ralph Alderson, Yinhua Yang, Syd Johnson, Paul Moore, Lioudmila Tchistiakova, Hans-Peter Gerber and Chad May
Timothy S. Fisher
Pfizer, Inc., San Diego, CA;
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Adam Root
Pfizer, Inc., Cambridge, MA;
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Bryan Peano
Pfizer, Inc., Pearl River, NY;
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Allison Rohner
Pfizer, Inc., San Diego, CA;
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Justin Lucas
Pfizer, Inc., Pearl River, NY;
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Mark Elliott
Pfizer, Inc., San Diego, CA;
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Konstantinos Tsaparikos
Pfizer, Inc., San Diego, CA;
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Hui Wang
Pfizer, Inc., San Diego, CA;
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Jonathan Golas
Pfizer, Inc., Pearl River, NY;
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Maria Gavriil
Pfizer, Inc., Pearl River, NY;
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Susan Benard
Pfizer, Inc., Cambridge, MA;
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Tao He
Pfizer, Inc., Cambridge, MA;
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Tracey Clark
Pfizer, Inc., Groton, CT;
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Nahor Haddish-Berhane
Pfizer, Inc., Groton, CT;
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Ralph Alderson
MacroGenics, Inc., Rockville, MD.
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Yinhua Yang
MacroGenics, Inc., Rockville, MD.
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Syd Johnson
MacroGenics, Inc., Rockville, MD.
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Paul Moore
MacroGenics, Inc., Rockville, MD.
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Lioudmila Tchistiakova
Pfizer, Inc., Cambridge, MA;
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Hans-Peter Gerber
Pfizer, Inc., Pearl River, NY;
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Chad May
Pfizer, Inc., Pearl River, NY;
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DOI: 10.1158/1538-7445.AM2015-2476 Published August 2015
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Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA

Abstract

Introduction: Strong evidence exists supporting the important role T-cells play in the immune response against tumors. Still, the ability to initiate tumor specific immune responses remains a challenge. We have developed a Dual-Affinity Re-Targeting (DART®) protein engineered with enhanced pharmacokinetic properties to extend in vivo half-life, and designed to engage and activate endogenous polyclonal T cell populations via the CD3 complex in the presence of P-cadherin expressing tumors. We designate this bispecific redirecting T-cell molecule as P-cadherin LP-DART. P-cadherin up-regulation has been reported in various tumors, including breast, gastric, endometrial, colorectal and pancreatic cancers, and is correlated with poor survival of patients.

Methods: The P-cadherin LP-DART was stably expressed by CHO cells and purified to homogeneity via standard antibody-purification methods. Functional in vitro studies were performed with a panel of human cancer cell lines and human T cells isolated from healthy donors. In vivo tumor growth inhibition studies were performed in immunodeficient athymic nude or NOD-scid IL2Rgammanull (NSG) mice bearing human tumor cell line- or patient derived-xenografts and human T-cells, and treated with P-cadherin LP-DART.

Results: P-cadherin LP-DART exhibited binding to a broad panel of cancer cell lines expressing various levels of endogenous cell surface P-cadherin, and comparable binding to a number of human donor derived T-cells expressing CD3. In the presence of T-cells, this bispecific molecule elicited P-cadherin expression level dependent cytotoxic T-lymphocyte (CTL) responses against the different tumor cell lines, and induced antigen dependent T-cell activation and cytokine release. P-cadherin LP-DART also demonstrated potent in vivo anti-tumor activity against implanted tumor xenografts. Significant tumor growth inhibition was observed across a range of potential indications that express P-cadherin. Measurement of in vivo pharmacodynamic markers support P-cadherin LP-DART mediated CTL infiltration and killing as the mechanism of tumor inhibition.

Conclusions: P-cadherin LP-DART displays potent in vitro and in vivo redirected T-cell activity against a broad panel of cancer cell lines expressing a range of cell surface P-cadherin levels. These data support further investigation of P-cadherin LP-DART as a potential novel therapeutic treatment for cancers expressing P-cadherin.

Citation Format: Timothy S. Fisher, Adam Root, Bryan Peano, Allison Rohner, Justin Lucas, Mark Elliott, Konstantinos Tsaparikos, Hui Wang, Jonathan Golas, Maria Gavriil, Susan Benard, Tao He, Tracey Clark, Nahor Haddish-Berhane, Ralph Alderson, Yinhua Yang, Syd Johnson, Paul Moore, Lioudmila Tchistiakova, Hans-Peter Gerber, Chad May. Bispecific redirected T-cell immunotherapy targeting P-cadherin expressing tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2476. doi:10.1158/1538-7445.AM2015-2476

  • ©2015 American Association for Cancer Research.
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Cancer Research: 75 (15 Supplement)
August 2015
Volume 75, Issue 15 Supplement
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Abstract 2476: Bispecific redirected T-cell immunotherapy targeting P-cadherin expressing tumors
Timothy S. Fisher, Adam Root, Bryan Peano, Allison Rohner, Justin Lucas, Mark Elliott, Konstantinos Tsaparikos, Hui Wang, Jonathan Golas, Maria Gavriil, Susan Benard, Tao He, Tracey Clark, Nahor Haddish-Berhane, Ralph Alderson, Yinhua Yang, Syd Johnson, Paul Moore, Lioudmila Tchistiakova, Hans-Peter Gerber and Chad May
Cancer Res August 1 2015 (75) (15 Supplement) 2476; DOI: 10.1158/1538-7445.AM2015-2476

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Abstract 2476: Bispecific redirected T-cell immunotherapy targeting P-cadherin expressing tumors
Timothy S. Fisher, Adam Root, Bryan Peano, Allison Rohner, Justin Lucas, Mark Elliott, Konstantinos Tsaparikos, Hui Wang, Jonathan Golas, Maria Gavriil, Susan Benard, Tao He, Tracey Clark, Nahor Haddish-Berhane, Ralph Alderson, Yinhua Yang, Syd Johnson, Paul Moore, Lioudmila Tchistiakova, Hans-Peter Gerber and Chad May
Cancer Res August 1 2015 (75) (15 Supplement) 2476; DOI: 10.1158/1538-7445.AM2015-2476
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