Targeting CD98 with IGN523: Unraveling the Multifaceted Approach to Combat AML

Acute myeloid leukemia (AML) is a prevalent form of leukemia in adults, causing a significant number of fatalities annually in the United States. The current standard of care (SOC) has limited treatment options and often results in poor clinical outcomes, highlighting the need for more effective therapies. CD98, a heterodimeric cell surface protein, is associated with various types of cancer and is linked to poor prognosis due to its high expression levels. Its role in integrin signaling and amino acid transport is crucial for tumor cell growth and metastasis.

A study has shown that IGN523, a humanized monoclonal antibody, targets CD98 and exhibits multiple mechanisms of action (MOAs), leading to strong anti-tumor effects in various leukemic models. The expression of CD98 was measured in AML patient bone marrow samples using flow cytometry, focusing on CD34+/CD33- progenitor cells and the more mature CD34+/CD33+ precursors. The anti-tumor effects of IGN523 were tested in 11 xenograft models, including five AML models, using mice with different immune-deficient backgrounds. The treatment involved IGN523 alone or in combination with SOC agents, with dose-response studies conducted in selected models.

IGN523's capacity to trigger NK-cell mediated antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent lysis was assessed. Additional in vitro studies explored its impact on lysosomal and mitochondrial membrane permeabilization, amino acid transport, tumor cell proliferation, and apoptosis. The results from flow cytometry indicated a differential expression of CD98 in AML bone marrow cells compared to healthy controls, with higher expression in the CD34+/CD33+ population.

In mice with established leukemic tumors, IGN523 was administered weekly at doses of 15 or 30 mg/kg, demonstrating significant tumor growth inhibition (TGI) in several models, with a clear dose-response relationship observed. The efficacy of IGN523 was comparable to or better than that of SOC agents such as cytarabine. In vitro findings revealed that IGN523 induces strong ADCC activity, causes lysosomal membrane permeabilization, and disrupts essential amino acid transport. It also inhibits cell proliferation and survival signaling pathways by reducing the phosphorylation of PRAS40 and p70s6K, leading to apoptosis.

The elevated expression of CD98 in AML cells, the pre-clinical success of IGN523 in xenograft models, and the discovery of its diverse MOAs provide a solid basis for its therapeutic application. Consequently, clinical trials are recommended to assess the efficacy and safety of IGN523 in treating AML patients.