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An Allosteric Anti-Tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma

64 Pages Posted: 3 Mar 2019 Last revised: 29 May 2019 Sneak Peek Status: Review Complete

See all articles by Henry R. Maun

Henry R. Maun

Genentech, Inc. - San Francisco - Departments of Early Discovery Biochemistry

Janet Jackman

Genentech, Inc. - San Francisco - Immunology Discovery

David F. Choy

Genentech, Inc. - San Francisco - Biomarker Discovery OMNI

Kelly M. Loyet

Genentech, Inc. - San Francisco - Biochemical and Cellular Pharmacology

Guiquan Jia

Genentech, Inc. - San Francisco - Biomarker Discovery OMNI

Amy Dressen

Genentech, Inc. - San Francisco - Human Genetics

Jason A. Hackney

Genentech, Inc. - San Francisco - Bioinformatics

Meire Bremer

Genentech, Inc. - San Francisco - OMNI Biomarker Development

Benjamin T. Walters

Genentech, Inc. - San Francisco - Biochemical and Cellular Pharmacology

Rajesh Vij

Genentech, Inc. - San Francisco - Antibody Engineering

Xiaocheng Chen

Genentech, Inc. - San Francisco - Antibody Engineering

Neil N. Trivedi

University of California, San Francisco (UCSF), School of Medicine, Department of Medicine; San Francisco Veterans Administration Health Care System - San Francisco Veterans Affairs Medical Center

Ashley Morando

Genentech, Inc. - San Francisco - Biochemical and Cellular Pharmacology

Michael T. Lipari

Genentech, Inc. - San Francisco - Departments of Early Discovery Biochemistry

Yvonne Franke

Genentech, Inc. - San Francisco - Biomolecular Resources

Xiumin Wu

Genentech, Inc. - San Francisco - Translational Immunology

John Liu

Genentech, Inc. - San Francisco - Translational Immunology

Ping Wu

Genentech, Inc. - San Francisco - Structural Biology

Diana Chang

Genentech, Inc. - San Francisco - Human Genetics

Luz Orozco Guerra

Genentech, Inc. - San Francisco - Human Genetics

Wyne P. Lee

Genentech, Inc. - San Francisco - Biomolecular Resources

Erin Christensen

Genentech, Inc. - San Francisco - Protein Chemistry

Manda Wong

Genentech, Inc. - San Francisco - Protein Chemistry

Racquel Corpuz

Genentech, Inc. - San Francisco - Protein Chemistry

Julie Q. Hang

Genentech, Inc. - San Francisco - Protein Chemistry

Jeff Lutman

Genentech, Inc. - San Francisco - Preclinical and Translational Pharmacokinetics

Siddharth Sukumaran

Genentech, Inc. - San Francisco - Preclinical and Translational Pharmacokinetics

Yan Wu

Genentech, Inc. - San Francisco - OMNI Biomarker Development

Lawrence B. Schwartz

Virginia Commonwealth University (VCU), School of Medicine, Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine

Magda Babina

Charité - Universitätsmedizin Berlin - Department of Dermatology and Allergy

Prescott G. Woodruff

Genentech, Inc. - San Francisco - Antibody Engineering; University of California, San Francisco (UCSF) - Division of Pulmonary, Critical Care, Allergy and Sleep Medicine

John V. Fahy

Genentech, Inc. - San Francisco - Antibody Engineering

Rahul Ahuja

Genentech, Inc. - San Francisco - Antibody Engineering; San Francisco Veterans Administration Health Care System - San Francisco Veterans Affairs Medical Center

George H. Caughey

Genentech, Inc. - San Francisco - Antibody Engineering; San Francisco Veterans Administration Health Care System - San Francisco Veterans Affairs Medical Center

Aija Kusi

Genentech, Inc. - San Francisco - Safety Assessment

Kathila R. Alatsis

Genentech, Inc. - San Francisco - Safety Assessment

Mark S. Dennis

Genentech, Inc. - San Francisco - OMNI Biomarker Development

Charles Eigenbrot

Genentech, Inc. - San Francisco - Translational Immunology

Daniel Kirchhofer

Genentech, Inc. - San Francisco - Departments of Early Discovery Biochemistry

Lawren C. Wu

Genentech, Inc. - San Francisco - Immunology Discovery

James T. Koerber

Genentech, Inc. - San Francisco - OMNI Biomarker Development

Tracy L. Staton

Genentech, Inc. - San Francisco - Bioinformatics

Brian L. Yaspan

Genentech, Inc. - San Francisco - Structural Biology

Joseph R. Arron

Genentech, Inc. - San Francisco - Immunology Discovery

Robert A. Lazarus

Genentech, Inc. - San Francisco - Departments of Early Discovery Biochemistry

Tangsheng Yi

Genentech, Inc. - San Francisco - Immunology Discovery

More...

Abstract

Severe asthma patients with low type 2 inflammation derive less clinical benefit from therapies targeting type 2 cytokines and have significant unmet medical needs. We show that mast cell tryptase is elevated in severe asthma patients, correlating with greater disease severity, but independent of type 2 biomarker status. Active β-tryptase allele count correlates with blood tryptase levels, and asthma patients carrying more active alleles benefit less from anti-IgE treatment. We generated a noncompetitive inhibitory antibody against human β-tryptase, which dissociates active tetramers into inactive monomers. A 2.15 Å crystal structure of a β-tryptase/antibody complex coupled with biochemical studies reveals the molecular basis for allosteric destabilization of both small and large interfaces required for tetramerization. Anti-tryptase potently blocks tryptase-dependent activity in a humanized mouse model, reducing IgE-mediated systemic anaphylaxis, and has favorable pharmacokinetics in cynomolgus monkeys. Our data provide the foundation for developing anti-tryptase as a clinical therapy for severe asthma.

Suggested Citation

Maun, Henry R. and Jackman, Janet and Choy, David F. and Loyet, Kelly M. and Jia, Guiquan and Dressen, Amy and Hackney, Jason A. and Bremer, Meire and Walters, Benjamin T. and Vij, Rajesh and Chen, Xiaocheng and Trivedi, Neil N. and Morando, Ashley and Lipari, Michael T. and Franke, Yvonne and Wu, Xiumin and Liu, John and Wu, Ping and Chang, Diana and Guerra, Luz Orozco and Lee, Wyne P. and Christensen, Erin and Wong, Manda and Corpuz, Racquel and Hang, Julie Q. and Lutman, Jeff and Sukumaran, Siddharth and Wu, Yan and Schwartz, Lawrence B. and Babina, Magda and Woodruff, Prescott G. and Fahy, John V. and Ahuja, Rahul and Caughey, George H. and Kusi, Aija and Alatsis, Kathila R. and Dennis, Mark S. and Eigenbrot, Charles and Kirchhofer, Daniel and Wu, Lawren C. and Koerber, James T. and Staton, Tracy L. and Yaspan, Brian L. and Arron, Joseph R. and Lazarus, Robert A. and Yi, Tangsheng, An Allosteric Anti-Tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma. Available at SSRN: https://ssrn.com/abstract=3345546 or http://dx.doi.org/10.2139/ssrn.3345546
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Henry R. Maun

Genentech, Inc. - San Francisco - Departments of Early Discovery Biochemistry

1 DNA Way
San Francisco, CA
United States

Janet Jackman

Genentech, Inc. - San Francisco - Immunology Discovery

1 DNA Way
San Francisco, CA
United States

David F. Choy

Genentech, Inc. - San Francisco - Biomarker Discovery OMNI

1 DNA Way
San Francisco, CA
United States

Kelly M. Loyet

Genentech, Inc. - San Francisco - Biochemical and Cellular Pharmacology

1 DNA Way
San Francisco, CA
United States

Guiquan Jia

Genentech, Inc. - San Francisco - Biomarker Discovery OMNI

1 DNA Way
San Francisco, CA
United States

Amy Dressen

Genentech, Inc. - San Francisco - Human Genetics

1 DNA Way
San Francisco, CA
United States

Jason A. Hackney

Genentech, Inc. - San Francisco - Bioinformatics

1 DNA Way
San Francisco, CA
United States

Meire Bremer

Genentech, Inc. - San Francisco - OMNI Biomarker Development

1 DNA Way
San Francisco, CA
United States

Benjamin T. Walters

Genentech, Inc. - San Francisco - Biochemical and Cellular Pharmacology

1 DNA Way
San Francisco, CA
United States

Rajesh Vij

Genentech, Inc. - San Francisco - Antibody Engineering

1 DNA Way
San Francisco, CA
United States

Xiaocheng Chen

Genentech, Inc. - San Francisco - Antibody Engineering

1 DNA Way
San Francisco, CA
United States

Neil N. Trivedi

University of California, San Francisco (UCSF), School of Medicine, Department of Medicine

San Francisco, CA
United States

San Francisco Veterans Administration Health Care System - San Francisco Veterans Affairs Medical Center

CA
United States

Ashley Morando

Genentech, Inc. - San Francisco - Biochemical and Cellular Pharmacology

1 DNA Way
San Francisco, CA
United States

Michael T. Lipari

Genentech, Inc. - San Francisco - Departments of Early Discovery Biochemistry

1 DNA Way
San Francisco, CA
United States

Yvonne Franke

Genentech, Inc. - San Francisco - Biomolecular Resources

1 DNA Way
San Francisco, CA
United States

Xiumin Wu

Genentech, Inc. - San Francisco - Translational Immunology

1 DNA Way
San Francisco, CA
United States

John Liu

Genentech, Inc. - San Francisco - Translational Immunology

1 DNA Way
San Francisco, CA
United States

Ping Wu

Genentech, Inc. - San Francisco - Structural Biology

1 DNA Way
San Francisco, CA
United States

Diana Chang

Genentech, Inc. - San Francisco - Human Genetics

1 DNA Way
San Francisco, CA
United States

Luz Orozco Guerra

Genentech, Inc. - San Francisco - Human Genetics

1 DNA Way
San Francisco, CA
United States

Wyne P. Lee

Genentech, Inc. - San Francisco - Biomolecular Resources

1 DNA Way
San Francisco, CA
United States

Erin Christensen

Genentech, Inc. - San Francisco - Protein Chemistry

1 DNA Way
San Francisco, CA
United States

Manda Wong

Genentech, Inc. - San Francisco - Protein Chemistry

1 DNA Way
San Francisco, CA
United States

Racquel Corpuz

Genentech, Inc. - San Francisco - Protein Chemistry

1 DNA Way
San Francisco, CA
United States

Julie Q. Hang

Genentech, Inc. - San Francisco - Protein Chemistry

1 DNA Way
San Francisco, CA
United States

Jeff Lutman

Genentech, Inc. - San Francisco - Preclinical and Translational Pharmacokinetics

1 DNA Way
San Francisco, CA
United States

Siddharth Sukumaran

Genentech, Inc. - San Francisco - Preclinical and Translational Pharmacokinetics

1 DNA Way
San Francisco, CA
United States

Yan Wu

Genentech, Inc. - San Francisco - OMNI Biomarker Development

1 DNA Way
San Francisco, CA
United States

Lawrence B. Schwartz

Virginia Commonwealth University (VCU), School of Medicine, Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine

Richmond, VA
United States

Magda Babina

Charité - Universitätsmedizin Berlin - Department of Dermatology and Allergy

Berlin
Germany

Prescott G. Woodruff

Genentech, Inc. - San Francisco - Antibody Engineering

1 DNA Way
San Francisco, CA
United States

University of California, San Francisco (UCSF) - Division of Pulmonary, Critical Care, Allergy and Sleep Medicine

San Francisco General Hospital
Box 2911
San Francisco, CA
United States

John V. Fahy

Genentech, Inc. - San Francisco - Antibody Engineering

1 DNA Way
San Francisco, CA
United States

Rahul Ahuja

Genentech, Inc. - San Francisco - Antibody Engineering

1 DNA Way
San Francisco, CA
United States

San Francisco Veterans Administration Health Care System - San Francisco Veterans Affairs Medical Center

CA
United States

George H. Caughey

Genentech, Inc. - San Francisco - Antibody Engineering

1 DNA Way
San Francisco, CA
United States

San Francisco Veterans Administration Health Care System - San Francisco Veterans Affairs Medical Center

CA
United States

Aija Kusi

Genentech, Inc. - San Francisco - Safety Assessment

1 DNA Way
San Francisco, CA
United States

Kathila R. Alatsis

Genentech, Inc. - San Francisco - Safety Assessment

1 DNA Way
San Francisco, CA
United States

Mark S. Dennis

Genentech, Inc. - San Francisco - OMNI Biomarker Development

1 DNA Way
San Francisco, CA
United States

Charles Eigenbrot

Genentech, Inc. - San Francisco - Translational Immunology

1 DNA Way
San Francisco, CA
United States

Daniel Kirchhofer

Genentech, Inc. - San Francisco - Departments of Early Discovery Biochemistry

1 DNA Way
San Francisco, CA
United States

Lawren C. Wu

Genentech, Inc. - San Francisco - Immunology Discovery

1 DNA Way
San Francisco, CA
United States

James T. Koerber

Genentech, Inc. - San Francisco - OMNI Biomarker Development

1 DNA Way
San Francisco, CA
United States

Tracy L. Staton

Genentech, Inc. - San Francisco - Bioinformatics

1 DNA Way
San Francisco, CA
United States

Brian L. Yaspan

Genentech, Inc. - San Francisco - Structural Biology

1 DNA Way
San Francisco, CA
United States

Joseph R. Arron

Genentech, Inc. - San Francisco - Immunology Discovery ( email )

1 DNA Way
San Francisco, CA
United States

Robert A. Lazarus

Genentech, Inc. - San Francisco - Departments of Early Discovery Biochemistry ( email )

1 DNA Way
San Francisco, CA
United States

Tangsheng Yi (Contact Author)

Genentech, Inc. - San Francisco - Immunology Discovery ( email )

1 DNA Way
San Francisco, CA
United States

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