Abstract LB-199: APVO436, a bispecific anti-CD123 x anti-CD3 ADAPTIR™ molecule for redirected T-cell cytotoxicity with limited cytokine release, is well tolerated in repeat dose toxicology studies in cynomolgus macaques
Authors: Comeau Michael R. , Gottschalk Rebecca , Daugherty Mollie , Sewell Toddy , Misher Lynda , Jeannette Bannink , Johnson Starrla , Parr Lara , Kumer John , Jablonski David , DeFrancesco Melissa , Bienvenue David , Hoyos Gabriela H. , McMahan Catherine J. , Gross Jane A. 
Published: August 2019

Abstract
Introduction: Depletion of CD123 over-expressing tumor cells may improve patient outcomes in several hematological malignancies including AML, MDS, ALL, CML, HCL and BPDCN. CD123 is infrequently expressed by normal cells making it an attractive tumor target, currently being pursued using several different approaches including T-cell engaging immunotherapies. Cytokine release syndrome (CRS) is a concern with T-cell engaging immunotherapies that may require complex clinical development strategies to manage safely. We have developed APVO436, a bispecific anti-CD123 x anti-CD3 ADAPTIR molecule for redirecting T-cell cytotoxicity to CD123-expressing tumor cells, currently in Phase I clinical testing in AML and MDS. A potential advantage of the ADAPTIR platform is reduced cytokine release compared to other formats (Mol Cancer Ther; 15(9):2155-65). We previously compared APVO436 activity to another CD123 x CD3 bispecific antibody containing the amino acid sequence of MGD006. We also demonstrated that APVO436 induces activation of AML patient T cells to kill endogenous tumor cells. Here we extend these studies to test the capacity of APVO436 to induce memory T-cell generation and describe the results of repeat dose toxicology studies in cynomolgus macaques.
Methods: Binding, T-cell activation and proliferation were assessed using flow cytometry. Cytotoxic activity was determined using chromium release and flow cytometry assays. Cytokine levels were assessed using multi-plex technology. Repeat dose toxicology studies were performed in cynomolgus macaques.
Results: In vitro, APVO436 induced lower levels of several T-cell cytokines while demonstrating similar levels of tumor cell lysis potency compared to other CD123 x CD3 bispecific antibodies. APVO436 induced extensive T-cell proliferation and the development of fully functional memory T cells with cytolytic function. Repeat-dose administration of APVO436 in NHP for 4 weeks by IV bolus injection induced transient changes in T lymphocytes and CD123+ leukocytes. Terminal elimination half-life ranged up to 108 hours with dose proportional exposure after first and last dose; some impact on serum concentration was observed from anti-drug antibodies at late time points.
Conclusions: APVO436 induced lower levels of T-cell cytokines associated with CRS compared to other CD123 x CD3 targeting bispecific antibodies and induced the generation of functional memory T cells. Repeat-dose toxicology studies in cynomolgus monkeys demonstrate that APVO436 has antibody-like clearance and volume of distribution parameters and a serum half-life of about 4.5 days. These data support clinical studies with APVO436 as a potential treatment for AML and other hematological malignancies with possible safety advantages over other CD123 targeting therapies.
Citation Format: Michael R. Comeau, Rebecca Gottschalk, Mollie Daugherty, Toddy Sewell, Lynda Misher, Bannink Jeannette, Starrla Johnson, Lara Parr, John Kumer, David Jablonski, Melissa DeFrancesco, David Bienvenue, Gabriela H. Hoyos, Catherine J. McMahan, Jane A. Gross. APVO436, a bispecific anti-CD123 x anti-CD3 ADAPTIR™ molecule for redirected T-cell cytotoxicity with limited cytokine release, is well tolerated in repeat dose toxicology studies in cynomolgus macaques [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 LB-199.