Abstract 4820: Pediatric preclinical testing consortium evaluation of the CD123 antibody drug conjugate, IMGN632, against xenograft models of pediatric acute lymphoblastic leukemia
Authors: Evans Kathryn , El-Zein Narimanne , Jones Connor , Erickson Stephen W. , Guo Yuelong , Teicher Beverly A. , Adams Sharlene , Zweidler-McKay Patrick A. , Smith Malcolm A. , Lock Richard B. 
Published: August 2019

Introduction: The characteristic expression of CD123 (the alpha subunit of the IL-3 receptor) in multiple hematological malignancies, including acute myeloid leukemia (AML), blastic plasmacytoid dendritic cell neoplasm and acute lymphoblastic leukemia (ALL) has made this antigen an attractive target for the development of new therapeutics. IMGN632 is a CD123 targeting antibody drug conjugate (ADC) comprised of a novel humanized antiCD123 antibody, G4723A, linked to a DNA monoalkylating payload of the indolindobenzodiazepine pseudodimer (IGN) class of cytotoxic compounds. IMGN632 demonstrates potent activity in AML samples at low concentrations with minimal impact on normal bone marrow progenitors, and antileukemia effects in AML xenograft models. A phase I clinical trial of IMGN632 in CD123 positive malignancies is ongoing (NCT033865). Therefore, it was of interest to test the in vivoefficacy of IMGN632 against preclinical models of pediatric ALL.

Methods: Pediatric ALL patient-derived xenografts (PDXs) grew in an orthotopic manner in NSG mice. Engraftment was assessed by the % human leukemic blasts in the peripheral blood (%huCD45+). Treatment commenced when the median %huCD45+exceeded 1%, and mice received IMGN632 or non-binding control ADC (240 µg/kg IV weekly x 3) or vehicle. An event was defined as the %huCD45+&gt;25% or leukemia-related morbidity. The Kaplan-Meier method was used to compare event-free survival (EFS) between treated (T) and control (C) groups. Stringent objective response measures were assigned to each mouse and reported as group medians. Cell surface CD123 levels were expressed as specific antibody binding capacity (sABC). IMGN632 was provided by ImmunoGen, Inc.

Results: IMGN632 was tested against 8 pediatric ALL PDXs (3 B-ALL; 3 MLLr-ALL; 2 Ph+-ALL) in which median cell surface CD123 expression ranged from 510-3375 sABC. NSG mice tolerated IMGN632 well with maximum average weight losses of 0.0-7.7% across treatment groups compared to 0.0-8.1% in vehicle controls. IMGN632 induced significant differences in EFS distribution compared to control in 8 of 8 PDXs. T-C values ranged from 9.8 to 64.8 days (T/C 3.0-9.4) and Maintained Complete Responses were observed in 6 of 8 PDXs. In 6 of 8 PDXs the median EFS of the IMGN632-treated groups extended &gt;5 weeks beyond the end of treatment. The control ADC did not significantly delay the progression of any PDX. There was no apparent correlation between CD123 sABC levels and in vivo activity with IMGN632 efficacy being observed across all CD123 expression levels.

Conclusions: IMGN632 exerted profound in vivo efficacy against PDXs derived from a broad range of ALL subtypes and with a broad range of CD123 antigen levels. These data strongly support the clinical investigation of IMGN632 in acute lymphoblastic leukemia. (Supported by NCI Grants CA199222 & CA199000)

Citation Format: Kathryn Evans, Narimanne El-Zein, Connor Jones, Stephen W. Erickson, Yuelong Guo, Beverly A. Teicher, Sharlene Adams, Patrick A. Zweidler-McKay, Malcolm A. Smith, Richard B. Lock. Pediatric preclinical testing consortium evaluation of the CD123 antibody drug conjugate, IMGN632, against xenograft models of pediatric acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4820.