title: Anti-EFNA4 Calicheamicin Conjugates Effectively Target Triple-Negative Breast and Ovarian Tumor-Initiating Cells to Result in Sustained Tumor Regressions.
abstract: OBJECTIVE
  Triple-negative breast cancer (TNBC) and ovarian cancer each comprise heterogeneous tumors, for which current therapies have little clinical benefit. Novel therapies that target and eradicate tumor-initiating cells (TIC) are needed to significantly improve survival.
  
  
  METHODS
  A panel of well-annotated patient-derived xenografts (PDX) was established, and surface markers that enriched for TIC in specific tumor subtypes were empirically determined. The TICs were queried for overexpressed antigens, one of which was selected to be the target of an antibody-drug conjugate (ADC). The efficacy of the ADC was evaluated in 15 PDX models to generate hypotheses for patient stratification.
  
  
  RESULTS
  We herein identified E-cadherin (CD324) as a surface antigen able to reproducibly enrich for TIC in well-annotated, low-passage TNBC and ovarian cancer PDXs. Gene expression analysis of TIC led to the identification of Ephrin-A4 (EFNA4) as a prospective therapeutic target. An ADC comprising a humanized anti-EFNA4 monoclonal antibody conjugated to the DNA-damaging agent calicheamicin achieved sustained tumor regressions in both TNBC and ovarian cancer PDX in vivo. Non-claudin low TNBC tumors exhibited higher expression and more robust responses than other breast cancer subtypes, suggesting a specific translational application for tumor subclassification.
  
  
  CONCLUSIONS
  These findings demonstrate the potential of PF-06647263 (anti-EFNA4-ADC) as a first-in-class compound designed to eradicate TIC. The use of well-annotated PDX for drug discovery enabled the identification of a novel TIC target, pharmacologic evaluation of the compound, and translational studies to inform clinical development.
authors.affiliation: Pfizer, Inc., Pearl River, New York. scott.dylla@stemcentrx.com marc.damelin@pfizer.com.
authors.forename: Marc
authors.initials: M
authors.lastname: Damelin
authors.affiliation: Stemcentrx, Inc., South San Francisco, California.
authors.forename: Alexander
authors.initials: A
authors.lastname: Bankovich
authors.affiliation: Stemcentrx, Inc., South San Francisco, California.
authors.forename: Albert
authors.initials: A
authors.lastname: Park
authors.affiliation: Stemcentrx, Inc., South San Francisco, California.
authors.forename: Jorge
authors.initials: J
authors.lastname: Aguilar
authors.affiliation: Stemcentrx, Inc., South San Francisco, California.
authors.forename: Wade
authors.initials: W
authors.lastname: Anderson
authors.affiliation: Stemcentrx, Inc., South San Francisco, California.
authors.forename: Marianne
authors.initials: M
authors.lastname: Santaguida
authors.affiliation: Stemcentrx, Inc., South San Francisco, California.
authors.forename: Monette
authors.initials: M
authors.lastname: Aujay
authors.affiliation: Stemcentrx, Inc., South San Francisco, California.
authors.forename: Sarah
authors.initials: S
authors.lastname: Fong
authors.affiliation: Pfizer, Inc., Pearl River, New York.
authors.forename: Kiran
authors.initials: K
authors.lastname: Khandke
authors.affiliation: Pfizer, Inc., Pearl River, New York.
authors.forename: Virginia
authors.initials: V
authors.lastname: Pulito
authors.affiliation: Pfizer, Inc., Pearl River, New York.
authors.forename: Elana
authors.initials: E
authors.lastname: Ernstoff
authors.affiliation: Stemcentrx, Inc., South San Francisco, California.
authors.forename: Paul
authors.initials: P
authors.lastname: Escarpe
authors.affiliation: Stemcentrx, Inc., South San Francisco, California.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Bernstein
authors.affiliation: Stemcentrx, Inc., South San Francisco, California.
authors.forename: Marybeth
authors.initials: M
authors.lastname: Pysz
authors.affiliation: Pfizer, Inc., Pearl River, New York.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Pfizer, Inc., Pearl River, New York.
authors.forename: Erik
authors.initials: E
authors.lastname: Upeslacis
authors.affiliation: Pfizer, Inc., Pearl River, New York.
authors.forename: Judy
authors.initials: J
authors.lastname: Lucas
authors.affiliation: Pfizer, Inc., Pearl River, New York.
authors.forename: Justin
authors.initials: J
authors.lastname: Lucas
authors.affiliation: Pfizer, Inc., Pearl River, New York.
authors.forename: Timothy
authors.initials: T
authors.lastname: Nichols
authors.affiliation: Stemcentrx, Inc., South San Francisco, California.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Loving
authors.affiliation: Stemcentrx, Inc., South San Francisco, California.
authors.forename: Orit
authors.initials: O
authors.lastname: Foord
authors.affiliation: Stemcentrx, Inc., South San Francisco, California.
authors.forename: Johannes
authors.initials: J
authors.lastname: Hampl
authors.affiliation: Stemcentrx, Inc., South San Francisco, California.
authors.forename: Robert
authors.initials: R
authors.lastname: Stull
authors.affiliation: Pfizer, Inc., Pearl River, New York.
authors.forename: Frank
authors.initials: F
authors.lastname: Barletta
authors.affiliation: Pfizer, Inc., Pearl River, New York.
authors.forename: Hadi
authors.initials: H
authors.lastname: Falahatpisheh
authors.affiliation: Pfizer, Inc., Pearl River, New York.
authors.forename: Puja
authors.initials: P
authors.lastname: Sapra
authors.affiliation: Pfizer, Inc., Pearl River, New York.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Gerber
authors.affiliation: Stemcentrx, Inc., South San Francisco, California. scott.dylla@stemcentrx.com marc.damelin@pfizer.com.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Dylla
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry; D058846:Antibodies, Monoclonal, Murine-Derived / Q000737:chemistry*; D000951:Antigens, Neoplasm / Q000737:chemistry; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry; D015195:Drug Design; D053281:Enediynes / Q000737:chemistry*; D036385:Ephrin-A4 / Q000737:chemistry*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011446:Prospective Studies; D011897:Random Allocation; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000617:Aminoglycosides; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000951:Antigens, Neoplasm; D053281:Enediynes; D036385:Ephrin-A4; C000609462:PF-06647263; C055955:calicheamicin gamma(1)I; D004247:DNA