Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults resulting in >10,000 deaths per year in the US. Limited treatment options and poor clinical response to current standard of care (SOC) necessitate development of more efficacious therapeutics. CD98 is a heterodimeric cell surface protein that is implicated in the pathogenesis of many hematological and solid malignancies and its elevated expression is correlated with poor prognosis and patient outcome. Previous studies demonstrated that CD98 functions both in integrin signaling and amino acid transport processes, which support the proliferation, anchorage-independence, invasion, and metastasis of tumor cells. Here we demonstrate that IGN523, a humanized monoclonal antibody targeting CD98, possesses multiple mechanisms of action (MOAs) and elicits potent anti-tumor activity against a variety of leukemic xenograft models.
CD98 expression was assessed on CD34+/CD33- progenitors and more mature CD34+/CD33+ precursors from AML patient bone marrow samples by flow cytometry. Anti-tumor efficacy of IGN523 treatment was evaluated across 11 lymphoma or leukemic xenograft models, including 5 AML, established in NOD/SCID, CB17, or NSG mice. Animals were treated with either IGN523 alone or in combination with SOC anti-tumor agents and dose-responses were performed in selected models. IGN523’s ability to elicit NK-cell mediated antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent tumor cell lysis was determined. Additional in vitro MOA studies investigated IGN523’s effect upon lysosomal and mitochondrial membrane permeabilization, amino acid transport, tumor cell proliferation and apoptosis.
Flow cytometry data demonstrate that CD98 is differentially expressed on CD34+/CD33- and CD34+/CD33+ AML bone marrow cells compared to healthy donors. In AML patients, CD98 expression was significantly increased on the CD34+/CD33+ cells versus the CD34+/CD33- population. Leukemic tumors were established in mice (100-200mm3 starting volumes) prior to weekly treatment with IGN523 dosed at 15 or 30 mg/kg. IGN523 elicited robust and significant tumor growth inhibition (TGI; p<0.01) in the majority of models including Ramos (87% TGI), HL-60 (70% TGI), KG-1 (53% TGI) and OCI-AML-3 (74% TGI). A well-defined IGN523 dose response (0.1 – 30 mg/kg) was also observed. IGN523 was at least as efficacious as SOC anti-tumor agents (e.g. cytarabine). In vitro data established that IGN523 elicits strong ADCC activity, induces lysosomal membrane permeabilization, and inhibits essential amino acid transport function. Moreover, IGN523 impedes cell proliferation/survival signaling cascades through reduction of PRAS40 and p70s6K phosphorylation, ultimately resulting in caspase-mediated apoptosis.
The combination of increased CD98 expression on AML cells, pre-clinical efficacy of IGN523 in xenograft models, and identification of diverse MOAs provide strong scientific rationale for therapeutic use in patients. Clinical trials are therefore warranted to evaluate the efficacy and safety of IGN523 in AML.
Hayes:Igenica, Inc.: Employment. Chinn:Igenica, Inc.: Employment. Cantor:Igenica, Inc.: Consultancy. Velilla:Igenica, Inc.: Employment. Ginsberg:Igenica, Inc.: Consultancy. van der Horst:Igenica, Inc.: Employment.
Asterisk with author names denotes non-ASH members.