LILRB4-targeting Antibody-Drug Conjugates for the Treatment of Acute Myeloid Leukemia

Mol Cancer Ther. 2020 Nov;19(11):2330-2339. doi: 10.1158/1535-7163.MCT-20-0407. Epub 2020 Sep 2.

Abstract

Acute myeloid leukemia (AML) is the most common and aggressive blood cancer in adults. In particular, significant unmet medical needs exist for effective treatment strategies for acute myelomonocytic leukemia (M4) and acute monocytic leukemia (M5) AML subtypes. Antibody-drug conjugates (ADC) are a promising drug class for AML therapy, as demonstrated by the FDA-approved anti-CD33 ADC, gemtuzumab ozogamicin (Mylotarg). However, CD33 is expressed in normal hematopoietic stem cells, highlighting the critical need to identify AML-specific targets to minimize the risk of potential adverse effects. We have demonstrated that the leukocyte immunoglobulin-like receptor subfamily B4 (LILRB4) is expressed at significantly higher levels on monocytic M4 and M5 AML cells than on normal counterparts. Here, we test whether LILRB4 is a promising ADC target to kill monocytic AML cells while sparing healthy counterparts. To this end, we generated ADCs from a humanized anti-LILRB4 mAb and the antimitotic payload, monomethyl auristatin F. The conjugates constructed were characterized and evaluated for LILRB4-specific cell killing potency, toxicity to progenitor cells, pharmacokinetics, and therapeutic efficacy. Our ADC linker technology platform efficiently generated homogeneous anti-LILRB4 ADCs with defined drug-to-antibody ratios. The homogeneous anti-LILRB4 ADCs demonstrated the capacity for LILRB4-mediated internalization, suitable physicochemical properties, and high cell killing potency against LILRB4-positive AML cells. Importantly, our data indicate that these ADCs spare normal progenitor cells. One of our homogeneous conjugates exerted a remarkable therapeutic effect and no significant toxicity in a xenograft mouse model of disseminated human AML. Our findings highlight the clinical potential of anti-LILRB4 ADCs in monocytic AML therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents, Immunological / chemistry
  • Antineoplastic Agents, Immunological / pharmacology*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Stability
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Immunoconjugates / chemistry
  • Immunoconjugates / pharmacology*
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / etiology
  • Leukemia, Myeloid, Acute / mortality
  • Leukemia, Myeloid, Acute / pathology
  • Membrane Glycoproteins / antagonists & inhibitors*
  • Mice
  • Protein Binding
  • Receptors, Immunologic / antagonists & inhibitors*
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / pharmacology
  • Treatment Outcome
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Immunological
  • Immunoconjugates
  • LILRB4 protein, human
  • Membrane Glycoproteins
  • Receptors, Immunologic
  • Recombinant Fusion Proteins