Abstract 7044: <i>In vitro</i> and <i>in vivo</i> activity of the CD127 monoclonal antibody 4A10 in preclinical models of childhood acute lymphoblastic leukemia

Abstract Background: 4A10 is a monoclonal antibody targeting CD127 (IL-7R alpha) under planned clinical development for treatment of patients with relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL). CD127 is endogenously expressed on normal/malignant T cells as a heterodimer with CD132 to form the IL-7 receptor. CD127 is also aberrantly expressed in CRLF2-rearranged B-ALL as part of the heterodimeric thymic stromal lymphopoietin receptor (TSLPR). 4A10 binds the extracellular domain of both wild type and mutant CD127 with high affinity and mediates its anticancer activity through a dual mechanism of action: (i) inhibition of IL-7 signaling, as assessed by phospho-STAT5 production, and (ii) induction of receptor-mediated cytotoxicity through antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), which can facilitate the killing of CD127+ cells. The role of CD127 in the development, maintenance, and relapse of T-ALL is well described. Extensive preclinical data with 4A10 have demonstrated robust anticancer activity in human T-ALL cell lines and patient-derived xenograft (PDX) models of early T-cell precursor (ETP) and other more mature subtypes. 4A10 has demonstrated single agent activity in chemo-naïve, chemo-resistant, and steroid-resistant T-ALL models, as well as augmented activity in combination with chemotherapy. As CD127 is expressed in other hematological cancers, we tested the hypothesis that 4A10 would also have robust anticancer activity across B-ALL subtypes. Results: In these preclinical studies, we first detected high expression of CD127 in six B-ALL genetic subtypes and potent 4A10-mediated ADCC in vitro against KOPN8, REH, and NALM6 cell lines. We then observed robust inhibition of leukemia proliferation and increased survival with 4A10 monotherapy treatment of CRLF2-rearranged Ph-like and Down syndrome-associated, BCR::ABL1, TCF3::PBX1, ETV6::RUNX1, and high-hyperdiploid ALL PDX models compared to vehicle. Single agent 4A10 treatment of steroid-resistant KOPN8 cell line xenograft mice further demonstrated in vivo activity with some augmentation on dexamethasone addition. Conclusions: CD127 is an attractive target with a low risk of ‘bystander toxicity’ given limited CD127 expression in normal tissues as assessed by tissue cross-reactivity studies. In recent non-human primate studies, 4A10 therapy had a tolerable clinical profile with modest and reversible reduction in normal peripheral blood T-lymphocytes. Given the robust activity of 4A10 against multiple B-ALL subtypes, we will seek to extend our planned Phase 1/2A clinical trial assessing the safety and therapeutic efficacy of single agent 4A10 in adults and children with r/r ALL. Ongoing preclinical studies are also evaluating the therapeutic potential of 4A10 against lymphoma and AML based on promising pilot efficacy data. Citation Format: Gisele O. Rodrigues, Priscila P. Zenatti, Joao M. Feitoza, Robert K. Chen, Uksha Saini, Julie A. Hixon, Ross A. Hamilton, Michael J. Heffernan, Jose A. Yunes, Phillip P. Breitfeld, Atul Varadhachary, Sarah K. Tasian, Scott K. Durum. In vitro and in vivo activity of the CD127 monoclonal antibody 4A10 in preclinical models of childhood acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7044.