An Anti-CD22- seco-CBI-Dimer Antibody-Drug Conjugate (ADC) for the Treatment of Non-Hodgkin Lymphoma That Provides a Longer Duration of Response than Auristatin-Based ADCs in Preclinical Models

Mol Cancer Ther. 2021 Feb;20(2):340-346. doi: 10.1158/1535-7163.MCT-20-0046. Epub 2020 Dec 3.

Abstract

We are interested in developing a second generation of antibody-drug conjugates (ADCs) for the treatment of non-Hodgkin lymphoma (NHL) that could provide a longer duration of response and be more effective in indolent NHL than the microtubule-inhibiting ADCs pinatuzumab vedotin [anti-CD22-vc-monomethyl auristatin E (MMAE)] and polatuzumab vedotin (anti-CD79b-vc-MMAE). Pinatuzumab vedotin (anti-CD22-vc-MMAE) and polatuzumab vedotin (anti-CD79b-vc-MMAE) are ADCs that contain the microtubule inhibitor MMAE. Clinical trial data suggest that these ADCs have promising efficacy for the treatment of NHL; however, some patients do not respond or become resistant to the ADCs. We tested an anti-CD22 ADC with a seco-CBI-dimer payload, thio-Hu anti-CD22-(LC:K149C)-SN36248, and compared it with pinatuzumab vedotin for its efficacy and duration of response in xenograft models and its ability to deplete normal B cells in cynomolgus monkeys. We found that anti-CD22-(LC:K149C)-SN36248 was effective in xenograft models resistant to pinatuzumab vedotin, gave a longer duration of response, had a different mechanism of resistance, and was able to deplete normal B cells better than pinatuzumab vedotin. These studies provide evidence that anti-CD22-(LC:K149C)-SN36248 has the potential for longer duration of response and more efficacy in indolent NHL than MMAE ADCs and may provide the opportunity to improve outcomes for patients with NHL.

MeSH terms

  • Aminobenzoates / pharmacology
  • Aminobenzoates / therapeutic use*
  • Animals
  • Cell Line, Tumor
  • Haplorhini
  • Humans
  • Immunoconjugates / pharmacology
  • Immunoconjugates / therapeutic use*
  • Lymphoma, Non-Hodgkin / drug therapy*
  • Oligopeptides / pharmacology
  • Oligopeptides / therapeutic use*
  • Sialic Acid Binding Ig-like Lectin 2 / metabolism*

Substances

  • Aminobenzoates
  • CD22 protein, human
  • Immunoconjugates
  • Oligopeptides
  • Sialic Acid Binding Ig-like Lectin 2
  • auristatin