In:
Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3344-3344
Abstract:
Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are common forms of adult hematologic malignancies with incidences of approximately 1-6/100.000/year. Progress in the management of AML and high-risk MDS has lagged behind other hematological malignancies, and, in particular, treatment for relapsed or refractory (R/R) disease and minimal residual disease (MRD) are needed to induce long-term remission. Here we describe the preclinical development of AFM28, a novel bispecific Innate Cell Engager (ICE ®) developed using the Redirected Optimized Cell Killing (ROCK ®) platform, designed to specifically activate NK cells and induce depletion of leukemic blasts and LSCs. Natural killer (NK) cell-based innate immunotherapy is emerging as a promising treatment option in AML and MDS based on the demonstrated susceptibility of leukemic blasts for NK cell killing and clinical activity of allogeneic NK cell therapy in R/R disease. Depletion of leukemic stem cells (LSCs) alongside leukemic blasts is considered a critical goal of treatment in order to eradicate MRD and prevent relapse. Accordingly, treatments that effectively target both cell types hold the potential to induce long-term remission in patients with AML or MDS. AFM28 binds the surface antigen CD123, which is almost universally expressed on blasts and LSCs in AML and MDS, and selectively targets CD16A expressed on NK cells, with no detectable binding to CD16B expressed on neutrophils. Through high affinity, bivalent binding to CD16A in a region distinct from the Fc binding site of IgGs, AFM28 remains stably bound to NK cells for extended periods and potently induces antibody-dependent cell-mediated cytotoxicity (ADCC) towards CD123+ AML and MDS cells. When compared with conventional anti-CD123 antibodies, including Fc-enhanced IgG1, AFM28 mediates more potent lysis of tumor cells even with low levels of CD123 expression. Furthermore, in contrast to conventional monoclonal CD123 antibodies, AFM28-induced lysis is not affected by the addition of competing IgG, which otherwise could impact efficacy. Similarly, ex vivo analysis of NK cell activation and inflammatory cytokine release in the ID.Flow human whole-blood loop system demonstrates that AFM28, compared with Fc-enhanced IgG1, produces 100-fold more potent NK cell activation associated with dose-dependent release of pro-inflammatory IL-6, TNFα, and IFNγ, concomitant with depletion of CD123+ plasmacytoid dendritic cells (pDCs) and basophils. In contrast, cytokine release was substantially lower than observed with a CD123-directed T cell-engaging bispecific antibody suggesting a low risk of cytokine release syndrome with AFM28. In vivo, AFM28 demonstrates a monoclonal antibody-like pharmacokinetic profile in mice and cynomolgus monkeys. A pre-clinical toxicology model in cynomolgus monkey suggested that AFM28 is safe and well tolerated and demonstrated pharmacodynamic activity. In summary, these data demonstrate AFM28 could be a novel treatment modality for AML and MDS that has good tolerability and the potential to effectively target MRD by depleting leukemic blasts and LSCs. AFM28 is currently being prepared for first-in-human clinical investigation. High affinity binding, potent induction of NK cell activation, and extended cell surface retention suggest AFM28 endows NK cells with CAR-like properties and may hold particular promise when combined with allogeneic NK cell therapy, for example within a pre-complexed NK cell product. Disclosures Götz: Affimed GmbH: Current Employment, Current holder of stock options in a privately-held company. Pahl: Affimed GmbH: Current Employment, Current holder of stock options in a privately-held company. Schmitt: Affimed GmbH: Research Funding. Müller: Affimed GmbH: Current Employment, Current holder of stock options in a privately-held company. Haneke: Affimed GmbH: Current Employment, Current holder of stock options in a privately-held company. Kozlowska: Affimed GmbH: Current Employment, Current holder of stock options in a privately-held company. Sarlang: Affimed GmbH: Current Employment, Current holder of stock options in a privately-held company. Knackmuss: Affimed GmbH: Current Employment, Current holder of stock options in a privately-held company. Peters: Affimed GmbH: Current Employment, Current holder of stock options in a privately-held company. Reusch: Affimed: Current Employment, Current holder of stock options in a privately-held company. Ross: Affimed GmbH: Current Employment, Current holder of stock options in a privately-held company. Nowak: AbbVie: Other: Investigator on funded clinical trial; Tolero Pharma, Pharmaxis, Apogenix: Research Funding; Affimed: Research Funding; Pharmaxis: Current holder of individual stocks in a privately-held company, Research Funding; Celgene: Honoraria; Takeda: Honoraria. Hofmann: Affimed GmbH: Research Funding. Merz: Affimed GmbH: Current Employment, Current holder of stock options in a privately-held company.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood-2021-152463
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2021
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
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