Conjugation of DM1 to anti-CD30 antibody has potential antitumor activity in CD30-positive hematological malignancies with lower systemic toxicity.

Abstract

An anti-CD30 antibody-drug conjugate incorporating the antimitotic agent DM1 and a stable SMCC linker, anti-CD30-MCC-DM1, was generated as a new antitumor drug candidate for CD30-positive hematological malignancies. Here, the in vitro and in vivo pharmacologic activities of anti-CD30-MCC-DM1 (also known as F0002-ADC) were evaluated and compared with ADCETRIS (brentuximab vedotin). Pharmacokinetics (PK) and the safety profiles in cynomolgus monkeys were assessed. Anti-CD30-MCC-DM1 was effective in in vitro cell death assays using CD30-positive lymphoma cell lines. We studied the properties of anti-CD30-MCC-DM1, including binding, internalization, drug release and actions. Unlike ADCETRIS, anti-CD30-MCC-DM1 did not cause a bystander effect in this study. In vivo, anti-CD30-MCC-DM1 was found to be capable of inducing tumor regression in subcutaneous inoculation of Karpas 299 (anaplastic large cell lymphoma), HH (cutaneous T-cell lymphoma) and L428 (Hodgkin's disease) cell models. The half-lives of 4 mg/kg and 12 mg/kg anti-CD30-MCC-DM1 were about 5 days in cynomolgus monkeys, and the tolerated dose was 30 mg/kg in non-human primates, supporting the tolerance of anti-CD30-MCC-DM1 in humans. These results suggest that anti-CD30-MCC-DM1 presents efficacy, safety and PK profiles that support its use as a valuable treatment for CD30-positive hematological malignancies.

• Authors: Yijun Shen, Tong Yang, Xuemei Cao, Yifan Zhang, Li Zhao, Hua Li, Teng Zhao, Jun Xu, Hengbin Zhang, Qingsong Guo, Junli Cai, Bei Gao, Helin Yu, Sicheng Yin, Ruiwen Song, Jingsong Wu, Lingyu Guan, Guanghao Wu, Li Jin, Yong Su, Yanjun Liu
• Journal: mAbs (MAbs) 2019 Aug/Sep Vol. 11 Issue 6 Pg. 1149-1161 ISSN: 1942-0870 [Electronic] United States
• PMID: 31161871 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Video-Audio Media)

Chemical References

• Antineoplastic Agents
• Immunoconjugates
• Ki-1 Antigen
• Brentuximab Vedotin

Topics

• Animals
• Antineoplastic Agents (immunology, pharmacology)
• Brentuximab Vedotin (immunology, pharmacology)
• Drug Evaluation, Preclinical
• Hematologic Neoplasms (drug therapy, immunology, pathology)
• Humans
• Immunoconjugates (immunology, pharmacology)
• Ki-1 Antigen (immunology)
• Lymphoma, Large-Cell, Anaplastic (drug therapy, immunology, pathology)
• Macaca fascicularis
• Mice
• Mice, SCID