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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Large Molecule Therapeutics

Nonclinical Development of Next-generation Site-specific HER2-targeting Antibody–drug Conjugate (ARX788) for Breast Cancer Treatment

Prathap Nagaraja Shastri, Jingjing Zhu, Lillian Skidmore, Xuejun Liang, Yanping Ji, Yi Gu, Feng Tian, Sulan Yao and Gang Xia
Prathap Nagaraja Shastri
1Ambrx, La Jolla, California.
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Jingjing Zhu
2NovoCodex Biopharmaceuticals Co., Shaoxing, China.
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Lillian Skidmore
1Ambrx, La Jolla, California.
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Xuejun Liang
2NovoCodex Biopharmaceuticals Co., Shaoxing, China.
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Yanping Ji
2NovoCodex Biopharmaceuticals Co., Shaoxing, China.
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Yi Gu
1Ambrx, La Jolla, California.
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Feng Tian
1Ambrx, La Jolla, California.
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Sulan Yao
1Ambrx, La Jolla, California.
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  • For correspondence: sulan.yao@ambrx.com xiagang@zmc-china.com
Gang Xia
2NovoCodex Biopharmaceuticals Co., Shaoxing, China.
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  • For correspondence: sulan.yao@ambrx.com xiagang@zmc-china.com
DOI: 10.1158/1535-7163.MCT-19-0692 Published September 2020
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Abstract

Conventional antibody–drug conjugates (ADC) utilize native surface-exposed lysines or cysteines on the antibody of interest to conjugate cytotoxic payload. The nonspecific conjugation results in a mixture with variable drug-to-antibody ratios (DAR), conjugation sites, and ADCs that are often unstable in systemic circulation. ARX788 is an ADC consisting of a HER2-targeting antibody site-specifically conjugated with a potent antitubulin cytotoxic drug-linker, AS269. The site-specific conjugation is achieved by first incorporating the nonnatural amino acid, para-acetyl phenylalanine (pAF), into the antibody, followed by covalent conjugation of AS269 to the pAF to form a highly stable oxime bond resulting in a DAR 2 ADC. ARX788 exhibits significant, dose-dependent antitumor activity against HER2- expressing breast and gastric xenograft tumors. Pharmacokinetic (PK) studies in multiple species showed the highly stable nature of ARX788 with overlapping PK profiles for the intact ADC and total antibody. Metabolism studies demonstrated that pAF-AS269 was the sole major metabolite of ARX788, with no evidence for the release of free drug often observed in conventional ADCs and responsible for adverse side effects. Furthermore, ARX788 demonstrated a favorable safety profile in monkeys with a highest nonseverely toxic dose of 10 mg/kg, which was well above the efficacious dose level observed in preclinical tumor models, thus supporting clinical development of ARX788.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2020;19:1822–32

  • Received July 12, 2019.
  • Revision received December 1, 2019.
  • Accepted June 2, 2020.
  • Published first June 4, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 19 (9)
September 2020
Volume 19, Issue 9
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Nonclinical Development of Next-generation Site-specific HER2-targeting Antibody–drug Conjugate (ARX788) for Breast Cancer Treatment
Prathap Nagaraja Shastri, Jingjing Zhu, Lillian Skidmore, Xuejun Liang, Yanping Ji, Yi Gu, Feng Tian, Sulan Yao and Gang Xia
Mol Cancer Ther September 1 2020 (19) (9) 1822-1832; DOI: 10.1158/1535-7163.MCT-19-0692

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Nonclinical Development of Next-generation Site-specific HER2-targeting Antibody–drug Conjugate (ARX788) for Breast Cancer Treatment
Prathap Nagaraja Shastri, Jingjing Zhu, Lillian Skidmore, Xuejun Liang, Yanping Ji, Yi Gu, Feng Tian, Sulan Yao and Gang Xia
Mol Cancer Ther September 1 2020 (19) (9) 1822-1832; DOI: 10.1158/1535-7163.MCT-19-0692
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Molecular Cancer Therapeutics
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