The bispecific innate cell engager AFM28 eliminates CD123⁺ leukemic stem and progenitor cells in AML and MDS

Area of Science:

• Hematology
• Immunology
• Oncology

Background:

• Durable remissions in acute myeloid leukemia (AML) and high-risk myelodysplastic neoplasms (MDS) require targeting of leukemic stem and progenitor cells (LSPCs).
• CD123 is a promising target on LSPCs and leukemic blasts, but prior targeting strategies have faced efficacy and safety challenges.

Purpose of the Study:

• To evaluate the preclinical efficacy and safety of the bispecific CD123/CD16A innate cell engager, AFM28.
• To assess AFM28's potential to overcome limitations of previous CD123-targeting therapies.

Main Methods:

• In vitro assessment of AFM28 activity against patient-derived AML and MDS LSPCs and blasts.
• Evaluation of AFM28-induced autologous and allogeneic natural killer (NK) cell activity in AML whole blood cultures.
• In vivo efficacy studies using xenograft mouse models.
• Preclinical safety and pharmacodynamic assessment in cynomolgus monkeys.

Main Results:

• AFM28 demonstrated superior in vitro activity against AML/MDS LSPCs and blasts compared to an Fc-enhanced CD123 antibody, particularly against CD123low and/or CD64+ cells.
• AFM28 induced autologous anti-leukemic activity by enhancing AML patient NK cell function, with further enhancement by allogeneic NK cells.
• Anti-leukemic activity was confirmed in vivo in xenograft models.
• AFM28 exhibited a favorable safety profile and pharmacodynamic activity in non-human primates.

Conclusions:

• AFM28 shows significant preclinical potential as a bispecific engager for treating AML and MDS.
• This therapy may reduce residual disease and promote long-term remissions with an improved safety profile.
• AFM28 warrants further clinical investigation for AML and MDS patients.