title: ImmunoPET helps predicting the efficacy of antibody-drug conjugates targeting TENB2 and STEAP1.
abstract: The efficacy of antibody-drug conjugates (ADCs) targeted to solid tumors depends on biological processes that are hard to monitor in vivo. 89Zr-immunoPET of the ADC antibodies could help understand the performance of ADCs in the clinic by confirming the necessary penetration, binding, and internalization. This work studied monomethyl auristatin E (MMAE) ADCs against two targets in metastatic castration-resistant prostate cancer, TENB2 and STEAP1, in four patient-derived tumor models (LuCaP35V, LuCaP70, LuCaP77, LuCaP96.1). Three aspects of ADC biology were measured and compared: efficacy was measured in tumor growth inhibition studies; target expression was measured by immunohistochemistry and flow cytometry; and tumor antibody uptake was measured with 111In-mAbs and gamma counting or with 89Zr-immunoPET. Within each model, the mAb with the highest tumor uptake showed the greatest potency as an ADC. Sensitivity between models varied, with the LuCaP77 model showing weak efficacy despite high target expression and high antibody uptake. Ex vivo analysis confirmed the in vivo results, showing a correlation between expression, uptake and ADC efficacy. We conclude that 89Zr-immunoPET data can demonstrate which ADC candidates achieve the penetration, binding, and internalization necessary for efficacy in tumors sensitive to the toxic payload.
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA, 94080, USA.
authors.forename: Simon-Peter
authors.initials: SP
authors.lastname: Williams
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA, 94080, USA.
authors.forename: Annie
authors.initials: A
authors.lastname: Ogasawara
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA, 94080, USA.
authors.forename: Jeff N
authors.initials: JN
authors.lastname: Tinianow
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA, 94080, USA.
authors.forename: Judith E
authors.initials: JE
authors.lastname: Flores
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA, 94080, USA.
authors.forename: David
authors.initials: D
authors.lastname: Kan
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA, 94080, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lau
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA, 94080, USA.
authors.forename: MaryAnn
authors.initials: M
authors.lastname: Go
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA, 94080, USA.
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Vanderbilt
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA, 94080, USA.
authors.forename: Herman S
authors.initials: HS
authors.lastname: Gill
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA, 94080, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Miao
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA, 94080, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Goldsmith
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA, 94080, USA.
authors.forename: Bonnee
authors.initials: B
authors.lastname: Rubinfeld
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA, 94080, USA.
authors.forename: Weiguang
authors.initials: W
authors.lastname: Mao
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA, 94080, USA.
authors.forename: Ron
authors.initials: R
authors.lastname: Firestein
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA, 94080, USA.
authors.forename: Shang-Fan
authors.initials: SF
authors.lastname: Yu
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA, 94080, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Marik
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA, 94080, USA.|Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, 9700RB, The Netherlands.
authors.forename: Anton G T
authors.initials: AG
authors.lastname: Terwisscha van Scheltinga
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000494:pharmacology; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D051379:Mice; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D009842:Oligopeptides / Q000494:pharmacology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D049268:Positron-Emission Tomography / Q000379:methods*; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy; D011868:Radioisotopes; D023041:Xenograft Model Antitumor Assays; D015040:Zirconium
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009842:Oligopeptides; D011868:Radioisotopes; C423567:TMEFF2 protein, human; D015040:Zirconium; D010088:Oxidoreductases; C432763:STEAP1 protein, human; C000615502:Zirconium-89; C495575:monomethyl auristatin E
keywords: STEAP1; TENB2; antibody-drug conjugates; immunoPET; zirconium-89