Targeting acute myeloid leukemia through antibody engineering: innovations in immunotherapy and combination regimens

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Abstract
Acute myeloid leukemia (AML), a heterogeneous and aggressive hematologic malignancy, remains challenging to treat due to high relapse rates, chemotherapy resistance, and the immunosuppressive tumor microenvironment (TME). While traditional therapies like chemotherapy and hematopoietic stem cell transplantation have improved outcomes, their efficacy is often limited by toxicity and disease recurrence. Recent advancements in antibody engineering have revolutionized AML immunotherapy, offering precision-targeted strategies to overcome these barriers. This narrative review explores the transformative role of monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), and bispecific antibodies (bsAbs) in redirecting immune effector cells, blocking immune checkpoints, and eradicating leukemic stem cells (LSCs). Key innovations include CD33-targeted gemtuzumab ozogamicin, CD123-directed bispecific engagers, and anti-CD47 agents that disrupt "don't eat me" signals. We highlight breakthroughs in antibody design-such as Fc optimization, trispecific constructs, and conditionally active biologics-that enhance specificity while minimizing on-target off-tumor toxicity. Clinical trials demonstrate promising results, including improved remission rates and survival in refractory/relapsed AML when combining antibodies with hypomethylating agents, venetoclax, or checkpoint inhibitors. However, challenges persist, including AML's genetic heterogeneity, adaptive immune evasion, and cytokine release syndrome (CRS) risks. Emerging strategies such as biomarker-driven personalization, TME modulation, and engineered NK-cell engagers are poised to address these limitations. By integrating preclinical insights with clinical data, this review underscores the potential of antibody-based combinatorial regimens to redefine AML therapy, offering durable responses and bridging the gap to curative approaches.

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