Broadening the Therapeutic Window of ADCs Using Site-Specific Bioconjugation Showcased by an MMAE-Containing Peptide Linker in a CD79b-Targeting ADC.

in Molecular cancer therapeutics by Philipp Probst, Isabella Attinger-Toller, Romain Bertrand, Ramona Stark, Roger Santimaria, Bernd Schlereth, Dragan Grabulovski, Philipp René Spycher

TLDR

  • A novel ADC technology generates an anti-CD79b-monomethyl auristatin E (MMAE) ADC with highly favorable biophysical properties, potent cytotoxicity, and improved antitumor efficacy compared to PV.

Abstract

The limitations of first-generation antibody-drug conjugate (ADC) technologies include suboptimal stability and efficacy, poor safety profiles, and challenging manufacturing processes. In this study, we describe an anti-CD79b-monomethyl auristatin E (MMAE) ADC generated using a novel peptide-based linker technology that allows for site-specific linker-payload conjugation to native antibodies in only one step. The ADC comprises native polatuzumab as the targeting antibody and a linker-payload consisting of a RKAA-peptide linker and MMAE. We compared our anti-CD79b-RKAA-MMAE ADC with polatuzumab vedotin (PV), the FDA-approved ADC for diffuse large B-cell lymphoma. In the clinic, PV shows significant instability in circulation, leading to strong and dose-limiting side effects, including neutropenia and peripheral neuropathy. The anti-CD79b-RKAA-MMAE ADC showed optimal biophysical properties with a well-defined drug-to-antibody ratio of 2. It demonstrated potent cytotoxicity in multiple cancer cell lines and was very stable in mouse, cynomolgus monkey, and human sera. The anti-CD79b-RKAA-MMAE conjugate showed equal antitumor efficacy at half the payload dose compared with PV in different xenograft models. At equal MMAE concentrations, greater tumor growth inhibition and a considerably longer duration of response were observed. Ultimately, the highest nonseverely toxic dose of 30 mg/kg was determined in a 4-week repeat-dose toxicology study in rats, which is a 3-fold higher ADC dose than reported for PV. In summary, the data show that our novel site-specific bioconjugation technology enabled the generation of an anti-CD79b-RKAA-MMAE ADC with highly favorable biophysical properties and a greatly improved therapeutic index by a factor of 4 to 6 compared with PV. The ADC may therefore represent a safe and efficacious alternative for patients with diffuse large B-cell lymphoma.

Overview

  • The study aims to develop a novel anti-CD79b-monomethyl auristatin E (MMAE) antibody-drug conjugate (ADC) using a peptide-based linker technology.
  • The ADC is compared with polatuzumab vedotin (PV), an FDA-approved ADC for diffuse large B-cell lymphoma.
  • The primary objective is to evaluate the biophysical properties, cytotoxicity, and antitumor efficacy of the novel ADC compared to PV.

Comparative Analysis & Findings

  • The novel ADC demonstrated optimal biophysical properties with a well-defined drug-to-antibody ratio of 2, whereas PV showed significant instability in circulation.
  • The novel ADC showed potent cytotoxicity in multiple cancer cell lines and was very stable in mouse, cynomolgus monkey, and human sera, whereas PV's stability in circulation led to dose-limiting side effects.
  • In xenograft models, the novel ADC showed equal antitumor efficacy at half the payload dose compared to PV and greater tumor growth inhibition and a longer duration of response at equal MMAE concentrations.

Implications and Future Directions

  • The novel site-specific bioconjugation technology may enable the generation of safer and more efficacious ADCs for patients with diffuse large B-cell lymphoma.
  • Future studies can investigate the novel ADC in larger animal models and clinical trials to confirm its safety and efficacy.
  • Additional research can explore the use of this technology for other tumor targets and diseases, expanding its therapeutic potential.
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