Development of Highly Optimized Antibody-Drug Conjugates against CD33 and CD123 for Acute Myeloid Leukemia

• Published in: Clinical cancer research 2021-01, Vol.27 (2), p.622-631
• Main Authors: Han, Yoon-Chi, Kahler, Jennifer, Piché-Nicholas, Nicole, Hu, Wenyue, Thibault, Stephane, Jiang, Fan, Leal, Mauricio, Katragadda, Madan, Maderna, Andreas, Dushin, Russell, Prashad, Nadira, Charati, Manoj B, Clark, Tracey, Tumey, L Nathan, Tan, Xingzhi, Giannakou, Andreas, Rosfjord, Edward, Gerber, Hans-Peter, Tchistiakova, Lioudmila, Loganzo, Frank, O'Donnell, Christopher J, Sapra, Puja
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Immunological - immunology; Antineoplastic Agents, Immunological - pharmacokinetics; Antineoplastic Agents, Immunological - therapeutic use; Area Under Curve; Cell Line, Tumor; Cell Survival - drug effects; Disease Models, Animal; Gemtuzumab - immunology; Gemtuzumab - pharmacokinetics; Gemtuzumab - therapeutic use; HL-60 Cells; Humans; Immunoconjugates - immunology; Immunoconjugates - pharmacokinetics; Immunoconjugates - therapeutic use; Interleukin-3 Receptor alpha Subunit - antagonists & inhibitors; Interleukin-3 Receptor alpha Subunit - immunology; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - immunology; Leukemia, Myeloid, Acute - metabolism; Macaca fascicularis; Mice; Sialic Acid Binding Ig-like Lectin 3 - antagonists & inhibitors; Sialic Acid Binding Ig-like Lectin 3 - immunology; Tumor Burden - drug effects; Xenograft Model Antitumor Assays - methods
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-20-2149

Mortality due to acute myeloid leukemia (AML) remains high, and the management of relapsed or refractory AML continues to be therapeutically challenging. The reapproval of Mylotarg, an anti-CD33-calicheamicin antibody-drug conjugate (ADC), has provided a proof of concept for an ADC-based therapeutic for AML. Several other ADCs have since entered clinical development of AML, but have met with limited success. We sought to develop a next-generation ADC for AML with a wide therapeutic index (TI) that overcomes the shortcomings of previous generations of ADCs. We compared the TI of our novel CD33-targeted ADC platform with other currently available CD33-targeted ADCs in preclinical models of AML. Next, using this next-generation ADC platform, we performed a head-to-head comparison of two attractive AML antigens, CD33 and CD123. Our novel ADC platform offered improved safety and TI when compared with certain currently available ADC platforms in preclinical models of AML. Differentiation between the CD33- and CD123-targeted ADCs was observed in safety studies conducted in cynomolgus monkeys. The CD33-targeted ADC produced severe hematologic toxicity, whereas minimal hematologic toxicity was observed with the CD123-targeted ADC at the same doses and exposures. The improved toxicity profile of an ADC targeting CD123 over CD33 was consistent with the more restricted expression of CD123 in normal tissues. We optimized all components of ADC design (i.e., leukemia antigen, antibody, and linker-payload) to develop an ADC that has the potential to translate into an effective new therapy against AML.