Convection enhanced delivery of EGFR targeting antibody-drug conjugates Serclutamab talirine and Depatux-M in glioblastoma patient-derived xenografts. (24th August 2022)

• Record Type: Journal Article
• Authors: Porath, Kendra A; Regan, Michael S; Griffith, Jessica I; Jain, Sonia; Stopka, Sylwia A; Burgenske, Danielle M; Bakken, Katrina K; Carlson, Brett L; Decker, Paul A; Vaubel, Rachael A; Dragojevic, Sonja; Mladek, Ann C; Connors, Margaret A; Hu, Zeng; He, Lihong; Kitange, Gaspar J; Gupta, Shiv K; Feldsien, Thomas M; Lefebvre, Didier R; Agar, Nathalie Y R; Eckel-Passow, Jeanette E; Reilly, Edward B; Elmquist, William F; Sarkaria, Jann N
• Is Part Of: Neuro-oncology advances. Volume 4(2022)Supplement 1
• Publication Date: 2022-08-24
• Subjects: antibody-drug conjugate -- convection-enhanced delivery -- Depatux-M -- glioblastoma -- Serclutamab talirine; 616.99481
• DOI: 10.1093/noajnl/vdac130
• Languages: English
• ISSNs: 2632-2498

Abstract

Abstract: Background: EGFR targeting antibody-drug conjugates (ADCs) are highly effective against EGFR-amplified tumors, but poor distribution across the blood–brain barrier (BBB) limits their efficacy in glioblastoma (GBM) when administered systemically. We studied whether convection-enhanced delivery (CED) can be used to safely infuse ADCs into orthotopic patient-derived xenograft (PDX) models of EGFRvIII mutant GBM. Methods: The efficacy of the EGFR-targeted ADCs depatuxizumab mafodotin (Depatux-M) and Serclutamab talirine (Ser-T) was evaluated in vitro and in vivo . CED was performed in nontumor and tumor-bearing mice. Immunostaining was used to evaluate ADC distribution, pharmacodynamic effects, and normal cell toxicity. Results: Dose-finding studies in orthotopic GBM6 identified single infusion of 2 μg Ser-T and 60 μg Depatux-M as safe and effective associated with extended survival prolongation (>300 days and 95 days, respectively). However, with serial infusions every 21 days, four Ser-T doses controlled tumor growth but was associated with lethal toxicity approximately 7 days after the final infusion. Limiting dosing to two infusions in GBM108 provided profound median survival extension of over 200 days. In contrast, four Depatux-M CED doses were well tolerated and significantly extended survival in both GBM6 (158 days) and GBM108 (310 days). In a toxicity analysis, Ser-T resulted in a profound loss in NeuN+ cells and markedly elevated GFAP staining, while Depatux-M was associated only with modest elevation in GFAP staining. Conclusion: CED of Depatux-M is well tolerated and results in extended survival in orthotopic GBM PDXs. In contrast, CED of Ser-T was associated with a much narrower therapeutic window.