Advertisement

Targeting Drug Conjugates to the Tumor Microenvironment: Probody Drug Conjugates

  • Jack Lin
  • Jason Sagert
Chapter
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

The tolerability and ultimately efficacy of ADCs are limited by 2 major issues: (1) antigen expression that is too low on tumors, resulting in insufficient toxin delivery to the tumor, especially within the confines of the clinical MTD established by linker/payload-driven off-target toxicity and (2) too much antigen expression on normal healthy tissues, resulting in on-target but off-tumor toxicity. In this chapter, we will review strategies for making antibody prodrugs that have been or could be used to selectively deliver drug to a tumor compared to normal tissues. These technologies have the potential to lower on-target, off-tumor toxicities and enable better efficacy of ADCs due to better target selection and the delivery of higher concentrations of drug to tumors.

Keywords

Ab drug conjugate (ADC) Linker/payload Linker/toxin Toxicity Mask MMP9 pH Probody Protease Tumor microenvironment 

References

  1. 1.
    Bross PF et al (2001) Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res 7(6):1490PubMedGoogle Scholar
  2. 2.
    de Claro RA et al (2012) U.S. Food and Drug Administration approval summary: brentuximab vedotin for the treatment of relapsed Hodgkin lymphoma or relapsed systemic anaplastic large-cell lymphoma. Clin Cancer Res 18(21):5845CrossRefPubMedGoogle Scholar
  3. 3.
    Amiri-Kordestani L et al (2014) FDA approval: ado-trastuzumab emtansine for the treatment of patients with HER2-positive metastatic breast cancer. Clin Cancer Res 20(17):4436CrossRefPubMedGoogle Scholar
  4. 4.
    Rowe JM, Lowenberg B (2013) Gemtuzumab ozogamicin in acute myeloid leukemia: a remarkable saga about an active drug. Blood 121(24):4838CrossRefPubMedGoogle Scholar
  5. 5.
    Donaghy H (2016) Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates. MAbs 8(4):659CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    de Goeij BE, Lambert JM (2016) New developments for antibody-drug conjugate-based therapeutic approaches. Curr Opin Immunol 40:14CrossRefPubMedGoogle Scholar
  7. 7.
    Saber H, Leighton JK (2015) An FDA oncology analysis of antibody-drug conjugates. Regul Toxicol Pharmacol 71(3):444CrossRefPubMedGoogle Scholar
  8. 8.
    Krop IE et al (2010) Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J Clin Oncol 28(6):2698CrossRefPubMedGoogle Scholar
  9. 9.
    Beck A et al (2017) Strategies and challenges for the next generation of antibody–drug conjugates. Nat Rev Drug Discov 16:315CrossRefPubMedGoogle Scholar
  10. 10.
    Saleh MN et al (2000) Phase I trial of the anti-Lewis Y drug Immunoconjugate BR96-doxorubicin in patients with Lewis Y-expressing epithelial tumors. J Clin Oncol 18:2282–2292CrossRefPubMedGoogle Scholar
  11. 11.
    Tijink BM et al (2006) A phase I dose escalation study with anti-CD44v6 bivatuzumab mertansine in patients with incurable squamous cell carcinoma of the head and neck or esophagus. Clin Cancer Res 12(20 Pt 1):6064CrossRefGoogle Scholar
  12. 12.
    Annunziata CM et al (2013) Phase 1, open-label study of MEDI-547 in patients with relapsed or refractory solid tumors. Investig New Drugs 31(1):77CrossRefGoogle Scholar
  13. 13.
    Tannock IF, Rotin D (1989) Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res 49(16):4373PubMedPubMedCentralGoogle Scholar
  14. 14.
    Zhang X et al (2010) Tumor pH and its measurement. J nuclear. Medicine 51:1167Google Scholar
  15. 15.
    Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4(11):891CrossRefPubMedGoogle Scholar
  16. 16.
    Liberti MV, Locasale JW (2016) The Warburg effect: how does it benefit Cancer cells? Trends Biochem Sci 41(3):211CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Vander Heiden MG et al (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930):1029CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Bhattacharya B et al (2016) The Warburg effect and drug resistance. Br J Pharmacol 173(6):970CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Sarkar CA et al (2002) Rational cytokine design for increased lifetime and enhanced potency using pH-activated “histidine switching”. Nat Biotechnol 20(9):908CrossRefPubMedGoogle Scholar
  20. 20.
    Chaparro-Riggers J et al (2012) Increasing serum half-life and extending cholesterol lowering in vivo by engineering antibody with pH-sensitive binding to PCSK9. J Biol Chem 287:11090CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Igawa T et al (2010) Antibody recycling by engineered pH-dependent antigen binding improves the duration of antigen neutralization. Nat Biotechnol 28(11):1203CrossRefPubMedGoogle Scholar
  22. 22.
    Huang L et al (2016) Preclinical evaluation of a next-generation, EGFR targeting ADC that promotes regression in KRAS or BRAF mutant tumors. Presented at American Association for Cancer Research Annual Meeting, New Orleans, Louisiana, April 16 - 20, 2016 http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=43ef76fe-c845-4b4b-8531-601f2b1c2c32&cKey=bb5dcf16-e379-432f-a72c-191183729d7b&mKey=%7b1D10D749-4B6A-4AB3-BCD4-F80FB1922267%7d
  23. 23.
    Turk B (2006) Targeting proteases: successes, failures and future prospects. Nat Rev Drug Discov 5:785CrossRefPubMedGoogle Scholar
  24. 24.
    Kessenbrock K et al (2010) Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141(1):52CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Sevenich L, Joyce JA (2014) Pericellular proteolysis in cancer. Genes Dev 28(21):2331CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Bugge TH et al (2009) Type II transmembrane serine proteases. J Biol Chem 284(35):23177CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Dass K et al (2008) Evolving role of uPA/uPAR system in human cancers. Cancer Treat Rev 34(2):122CrossRefPubMedGoogle Scholar
  28. 28.
    Murphy G (2008) The ADAMs: signalling scissors in the tumour microenvironment. Nat Rev Cancer 8(12):929CrossRefPubMedGoogle Scholar
  29. 29.
    Olson OC, Joyce JA (2015) Cysteine cathepsin proteases: regulators of cancer progression and therapeutic response. Nat Rev Cancer 15(12):712CrossRefPubMedGoogle Scholar
  30. 30.
    Coussens LM et al (2002) Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295(5564):2387CrossRefPubMedGoogle Scholar
  31. 31.
    Appleby TC et al (2017) Biochemical characterization and structure determination of a potent, selective antibody inhibitor of human MMP9. J Biol Chem 292(16):6810–6682CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Marshall DC et al (2015) Selective allosteric inhibition of MMP9 is efficacious in preclinical models of ulcerative colitis and colorectal Cancer. PLoS One 10(5):e0127063CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Metz S et al (2012) Bispecific antibody derivatives with restricted binding functionalities that are activated by proteolytic processing. Protein Eng Des Sel 25:571–580CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Onuoha SC (2015) Rational design of Antirheumatic Prodrugs specific for sites of inflammation. Arthritis Rheumatol 67:2662–2672CrossRefGoogle Scholar
  35. 35.
    Donaldson JM et al (2009) Design and development of masked therapeutic antibodies to limit off-target effects: application to an anti-EGFR antibodies. Cancer Biol Ther 8:2147–2152CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Podust VN (2016) Extension of in vivo half-life of biologically active molecules by XTEN protein polymers. J Control Release 240:52–66CrossRefPubMedGoogle Scholar
  37. 37.
    Desnoyers LR et al (2013) Tumor-specific activation of an EGFR-targeting Probody enhances therapeutic index. Sci Transl Med 5:207ra144CrossRefPubMedGoogle Scholar
  38. 38.
    Polu KR, Lowman HB (2014) Probody therapeutics for targeting antibodies to diseased tissue. Expert Opin Biol Ther 14:1049–1053CrossRefPubMedGoogle Scholar
  39. 39.
    Singh S et al (2016) Preclinical development of a probody drug conjugate (PDC) targeting CD71 for the treatment of multiple cancers. Presented at American Association for Cancer Research Annual Meeting, New Orleans, Louisiana, April 16 - 20, 2016. http://cytomx.com/wp-content/uploads/2016/04/Preclinical-Development-of-a-ProbodyTM-Drug-Conjugate-PDC-Targeting-CD71-for-the-Treatment-of-Multiple-Cancers-AACR-2016.pdf
  40. 40.
    Weaver AY et al (2015) Development of a probody drug conjugate (PDC) targeting CD166 for the treatment of multiple cancers. Presented at AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics Boston, Massachusetts, November 5 - 9, 2015 http://cytomx.com/wp-content/uploads/2015/11/20151104_CD166_AACR_NCI_EORTC_poster_TO_PRINT_FINAL.pdf
  41. 41.
    Takebe N et al (2014) Targeting notch signaling pathway in cancer: clinical development advances and challenges. Pharmacol Ther 141:140–149CrossRefPubMedGoogle Scholar
  42. 42.
    Wei P et al (2010) Evaluation of selective gamma-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design. Mol Cancer Ther 9(6):1618–1628CrossRefPubMedGoogle Scholar
  43. 43.
    Dumortier A et al (2010) Atopic dermatitis-like disease and associated lethal myeloproliferative disorder arise from loss of notch signaling in the murine skin. PLoS One 5(2):e9258CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Sagert J et al (2013) Tumor-specific inhibition of Jagged-dependent notch signaling using a Probody™ Therapeutic. Presented at AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, Boston, MA, October 19-23, 2013. Mol Cancer Ther 2013;12(11 Suppl):C158Google Scholar
  45. 45.
    Sagert J et al (2014) Transforming Notch ligands into tumor-antigen targets: a probody-drug conjugate (PDC) targeting Jagged 1 and Jagged 2. Presented at AACR Annual Meeting, San Diego, CA April 5-9, 2014. Cancer Res 2014;74(19 Suppl):Abstract 2665CrossRefGoogle Scholar
  46. 46.
    Weidle UH et al (2010) ALCAM/CD166: cancer-related issues. Cancer Genomics Proteomics 7(5):231–243PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.CytomX Therapeutics, Inc.South San FranciscoUSA

Personalised recommendations