Design and Preclinical Evaluation of a Novel B7-H4-Directed Antibody-Drug Conjugate, AZD8205, Alone and in Combination with the PARP1-Selective Inhibitor AZD5305

  • Clin Cancer Res. 2023 Mar 14;29(6):1086-1101. doi: 10.1158/1078-0432.CCR-22-2630.
Krista Kinneer  1 ,  Philipp Wortmann  2 ,  Zachary A Cooper  1 ,  Niall J Dickinson  3 ,  Luke Masterson  3 ,  Thais Cailleau  3 ,  Ian Hutchinson  3 ,  Balakumar Vijayakrishnan  3 ,  Mary McFarlane  4 ,  Kathryn Ball  4 ,  Michael Davies  5 ,  Arthur Lewis  4 ,  Yue Huang  6 ,  Anton I Rosenbaum  6 ,  Jiaqi Yuan  6 ,  Jon Chesebrough  1 ,  Judith Anderton  5 ,  Noel Monks  1 ,  Steven Novick  7 ,  Jixin Wang  1 ,  Nazzareno Dimasi  1 ,  R James Christie  1 ,  Darrin Sabol  1 ,  Frances Anne Tosto  1 ,  Yann Wallez  5 ,  Elisabetta Leo  5 ,  Mark R Albertella  5 ,  Anna D Staniszewska  5 ,  David A Tice  1 ,  Philip W Howard  3 ,  Nadia Luheshi  5 ,  Puja Sapra  1
Affiliations
  • 1. Oncology R&D, AstraZeneca, Gaithersburg, Maryland.
  • 2. Oncology R&D, AstraZeneca, Munich, Germany.
  • 3. Oncology R&D, AstraZeneca, London, United Kingdom.
  • 4. BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom.
  • 5. Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
  • 6. BioPharmaceuticals R&D, AstraZeneca, South San Francisco, California.
  • 7. BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland.
PMID: 36355054 DOI: 10.1158/1078-0432.CCR-22-2630
Abstract

Purpose: We evaluated the activity of AZD8205, a B7-H4-directed antibody-drug conjugate (ADC) bearing a novel Topoisomerase I inhibitor (TOP1i) payload, alone and in combination with the PARP1-selective inhibitor AZD5305, in preclinical models.

Experimental design: IHC and deep-learning-based image analysis algorithms were used to assess prevalence and intratumoral heterogeneity of B7-H4 expression in human Tumors. Several TOP1i-ADCs, prepared with Val-Ala or Gly-Gly-Phe-Gly Peptide Linkers, with or without a PEG8 spacer, were compared in biophysical, in vivo efficacy, and rat toxicology studies. AZD8205 mechanism of action and efficacy studies were conducted in human Cancer cell line and patient-derived xenograft (PDX) models.

Results: Evaluation of IHC-staining density on a per-cell basis revealed a range of heterogeneous B7-H4 expression across patient Tumors. This informed selection of bystander-capable Val-Ala-PEG8-TOP1i payload AZ14170133 and development of AZD8205, which demonstrated improved stability, efficacy, and safety compared with other linker-payload ADCs. In a study of 26 PDX Tumors, single administration of 3.5 mg/kg AZD8205 provided a 69% overall response rate, according to modified RECIST criteria, which correlated with homologous recombination repair (HRR) deficiency (HRD) and elevated levels of B7-H4 in HRR-proficient models. Addition of AZD5305 sensitized very low B7-H4-expressing Tumors to AZD8205 treatment, independent of HRD status and in models representing clinically relevant mechanisms of PARPi resistance.

Conclusions: These data provide evidence for the potential utility of AZD8205 for treatment of B7-H4-expressing Tumors and support the rationale for an ongoing phase 1 clinical study (NCT05123482). See related commentary by Pommier and Thomas, p. 991.

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