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The D3-GPC2-PBD ADC is Potently Efficacious Against Neuroblastoma and SCLC Via Engagement of a Conformational GPC2 Epitope

86 Pages Posted: 18 Sep 2020 Publication Status: Under Review

See all articles by Swetha Raman

Swetha Raman

Hospital for Sick Children Research Institute - Program in Molecular Medicine

Samantha N. Buongervino

Children’s Hospital of Philadelphia - Division of Oncology; University of Pennsylvania - Center for Childhood Cancer Research

Maria Lane

Children’s Hospital of Philadelphia - Division of Oncology; University of Pennsylvania - Center for Childhood Cancer Research

Doncho V. Zhelev

University of Pittsburgh - Department of Medicine

Zhongyu Zhu

National Cancer Institute - Cancer and Inflammation Program

Hong Cui

Hospital for Sick Children Research Institute - Program in Molecular Medicine

Benjamin Martinez

University of Pennsylvania - Department of Pathology and Lab Medicine

Daniel Martinez

Children's Hospital of Philadelphia - Department of Pathology

Yanping Wang

National Cancer Institute - Cancer and Inflammation Program

Kristen A. Upton

Children's Hospital of Philadelphia - Division of Oncology

Khushbu Patel

Children's Hospital of Philadelphia - Department of Bioinformatics and Health Informatics

Komal S. Rathi

University of Pennsylvania - The Center for Data Driven Discovery in Biomedicine

Carmen T. Navia

Integral Molecular

Daniel B. Harmon

Integral Molecular

Bruce Pawel

Children's Hospital Los Angeles - Department of Pathology and Laboratory Medicine; University of Southern California - Keck School of Medicine

Dimiter Dimitrov

University of Pittsburgh - Department of Medicine

John M. Maris

Children’s Hospital of Philadelphia - Division of Oncology; Children’s Hospital of Philadelphia - Center for Childhood Cancer Research; University of Pennsylvania - Perelman School of Medicine

Jean-Philippe Julien

Hospital for Sick Children Research Institute - Program in Molecular Medicine

Kristopher Bosse

Children’s Hospital of Philadelphia - Division of Oncology; University of Pennsylvania - Center for Childhood Cancer Research; University of Pennsylvania - Department of Pediatrics

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Abstract

The signaling co-receptor heparan sulfate proteoglycan GPC2 is a MYCN-activated, differentially-expressed cell surface oncoprotein and candidate immunotherapeutic target in neuroblastoma. Here we build on GPC2’s attributes as a robust target for immune-based therapies by finding it is highly expressed on the most clinically aggressive human neuroblastomas and small cell lung cancers (SCLCs), with highly enriched expression in the tumor stem cell compartment. A GPC2 directed antibody-drug conjugate (ADC; D3-GPC2-PBD) induces robust and durable tumor regressions in a panel of neuroblastoma and SCLC preclinical models with diverse oncogenic drivers via induction of DNA damage and apoptosis, as well as potent bystander cell killing. Finally, we illustrate that this ADC binds a tumor specific, conformation dependent epitope of the core human and murine GPC2 proteins explaining its tumor specificity and therapeutic tolerability. These studies provide the preclinical data to support the clinical translation of ADCs targeting GPC2.

Keywords: Glypican, neuroblastoma, small-cell lung cancer, antibody-drug conjugate, MYCN

Suggested Citation

Raman, Swetha and Buongervino, Samantha N. and Lane, Maria and Zhelev, Doncho V. and Zhu, Zhongyu and Cui, Hong and Martinez, Benjamin and Martinez, Daniel and Wang, Yanping and Upton, Kristen A. and Patel, Khushbu and Rathi, Komal S. and Navia, Carmen T. and Harmon, Daniel B. and Pawel, Bruce and Dimitrov, Dimiter and Maris, John M. and Julien, Jean-Philippe and Bosse, Kristopher, The D3-GPC2-PBD ADC is Potently Efficacious Against Neuroblastoma and SCLC Via Engagement of a Conformational GPC2 Epitope (September 2020). Available at SSRN: https://ssrn.com/abstract=3673604 or http://dx.doi.org/10.2139/ssrn.3673604
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Swetha Raman

Hospital for Sick Children Research Institute - Program in Molecular Medicine ( email )

555 University Ave
Toronto, Ontario M5G 1X8
Canada

Samantha N. Buongervino

Children’s Hospital of Philadelphia - Division of Oncology ( email )

34th Street and Civic Center Boulevard
Philadelphia, PA 19104-4399
United States

University of Pennsylvania - Center for Childhood Cancer Research ( email )

34th St and Civic Center Blvd
Philadelphia, PA 19104
United States

Maria Lane

Children’s Hospital of Philadelphia - Division of Oncology ( email )

34th Street and Civic Center Boulevard
Philadelphia, PA 19104-4399
United States

University of Pennsylvania - Center for Childhood Cancer Research ( email )

34th St and Civic Center Blvd
Philadelphia, PA 19104
United States

Doncho V. Zhelev

University of Pittsburgh - Department of Medicine ( email )

United States

Zhongyu Zhu

National Cancer Institute - Cancer and Inflammation Program ( email )

Frederick, MD
United States

Hong Cui

Hospital for Sick Children Research Institute - Program in Molecular Medicine

555 University Ave
Toronto, Ontario M5G 1X8
Canada

Benjamin Martinez

University of Pennsylvania - Department of Pathology and Lab Medicine ( email )

34th Street and Civic Center Boulevard
Philadelphia, PA 19104-4399
United States

Daniel Martinez

Children's Hospital of Philadelphia - Department of Pathology

Yanping Wang

National Cancer Institute - Cancer and Inflammation Program

Frederick, MD
United States

Kristen A. Upton

Children's Hospital of Philadelphia - Division of Oncology ( email )

34th Street and Civic Center Boulevard
Philadelphia, PA 19104-4399
United States

Khushbu Patel

Children's Hospital of Philadelphia - Department of Bioinformatics and Health Informatics

United States

Komal S. Rathi

University of Pennsylvania - The Center for Data Driven Discovery in Biomedicine ( email )

34th Street and Civic Center Boulevard
Philadelphia, PA 19104-4399
United States

Carmen T. Navia

Integral Molecular

3711 Market St #900
Philadelphia, PA 19104
United States

Daniel B. Harmon

Integral Molecular

3711 Market St #900
Philadelphia, PA 19104
United States

Bruce Pawel

Children's Hospital Los Angeles - Department of Pathology and Laboratory Medicine ( email )

University of Southern California - Keck School of Medicine ( email )

Los Angeles, CA 90089
United States

Dimiter Dimitrov

University of Pittsburgh - Department of Medicine ( email )

United States

John M. Maris

Children’s Hospital of Philadelphia - Division of Oncology ( email )

34th Street and Civic Center Boulevard
Philadelphia, PA 19104-4399
United States

Children’s Hospital of Philadelphia - Center for Childhood Cancer Research ( email )

34th St and Civic Center Blvd
Philadelphia, PA 19104
United States

University of Pennsylvania - Perelman School of Medicine ( email )

423 Guardian Drive
Philadelphia, PA 19104
United States

Jean-Philippe Julien

Hospital for Sick Children Research Institute - Program in Molecular Medicine ( email )

555 University Ave
Toronto, Ontario M5G 1X8
Canada

Kristopher Bosse (Contact Author)

Children’s Hospital of Philadelphia - Division of Oncology ( email )

34th Street and Civic Center Boulevard
Philadelphia, PA 19104-4399
United States

University of Pennsylvania - Center for Childhood Cancer Research ( email )

34th St and Civic Center Blvd
Philadelphia, PA 19104
United States

University of Pennsylvania - Department of Pediatrics ( email )

34th Street & Civic Center Boulevard
Philadelphia, PA 19104
United States

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