Antitumor activity and toxicity of anti-HER2 immunoRNase scFv 4D5-dibarnase in mice bearing human breast cancer xenografts

Taras G. Balandin, Evelina Edelweiss, Natalia V. Andronova, Elena M. Treshalina, Alexander M. Sapozhnikov, Sergey M. Deyev

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Summary: Ribonucleases (RNases) are a non-mutagenic alternative to harmful DNA-damaging anticancer drugs. Targeting of RNases with antibodies to surface antigens that are selectively expressed on tumor cells endows specificity to the cytotoxic actions of RNases. Barnase, a ribonuclease from Bacillus amyloliquefaciens, is a promising candidate for targeted delivery to cancer cells because of its insusceptibility to the ubiquitous cytoplasmic ribonuclease inhibitor, and its high stability and catalytic activity. Here, we characterized in vitro and in vivo an immunoRNase, scFv 4D5-dibarnase, which consists of two barnase molecules that are fused serially to the single-chain variable fragment (scFv) of humanized 4D5 antibody. The latter is directed against the extracellular domain of human epidermal growth factor receptor 2 (HER2), a cancer marker that is overexpressed in many human carcinomas. The scFv 4D5-dibarnase exerted a specific cytotoxic effect on HER2-overexpressing SKBR-3 and BT-474 human breast carcinoma cells (IC50=4.1 and 2.4 nM, respectively) via induction of apoptosis. Ten doses of 0.7 mg/kg scFv 4D5-dibarnase to BALB/c nude mice that bore SKBR-3 human breast cancer xenografts resulted in a 76% reduction in tumor growth. A single injection of scFv 4D5-dibarnase at a total course dose of 7 mg/kg did not cause severe side effects in BALB/c nude or BDF1 mice. The cytotoxicity and selectivity of scFv 4D5-dibarnase merit consideration of this immunoRNase as a potent anticancer agent.

Original languageEnglish
Pages (from-to)22-32
Number of pages11
JournalInvestigational New Drugs
Volume29
Issue number1
DOIs
Publication statusPublished - Feb 2011
Externally publishedYes

Fingerprint

Ribonucleases
Heterografts
Breast Neoplasms
Neoplasms
Antibodies, Monoclonal, Humanized
Single-Chain Antibodies
Surface Antigens
Nude Mice
Antineoplastic Agents
Inhibitory Concentration 50
Apoptosis
Carcinoma
Injections
human ERBB2 protein
immunoRNase scFv 4D5-dibarnase
Antibodies
DNA
Growth
Pharmaceutical Preparations
Bacillus amyloliquefaciens ribonuclease

Keywords

  • Antibody
  • Cancer
  • ImmunoRNase
  • Mouse
  • Ribonuclease
  • Toxicity

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

Antitumor activity and toxicity of anti-HER2 immunoRNase scFv 4D5-dibarnase in mice bearing human breast cancer xenografts. / Balandin, Taras G.; Edelweiss, Evelina; Andronova, Natalia V.; Treshalina, Elena M.; Sapozhnikov, Alexander M.; Deyev, Sergey M.

In: Investigational New Drugs, Vol. 29, No. 1, 02.2011, p. 22-32.

Research output: Contribution to journalArticle

Balandin, Taras G. ; Edelweiss, Evelina ; Andronova, Natalia V. ; Treshalina, Elena M. ; Sapozhnikov, Alexander M. ; Deyev, Sergey M. / Antitumor activity and toxicity of anti-HER2 immunoRNase scFv 4D5-dibarnase in mice bearing human breast cancer xenografts. In: Investigational New Drugs. 2011 ; Vol. 29, No. 1. pp. 22-32.
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AU - Balandin, Taras G.

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AU - Andronova, Natalia V.

AU - Treshalina, Elena M.

AU - Sapozhnikov, Alexander M.

AU - Deyev, Sergey M.

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AB - Summary: Ribonucleases (RNases) are a non-mutagenic alternative to harmful DNA-damaging anticancer drugs. Targeting of RNases with antibodies to surface antigens that are selectively expressed on tumor cells endows specificity to the cytotoxic actions of RNases. Barnase, a ribonuclease from Bacillus amyloliquefaciens, is a promising candidate for targeted delivery to cancer cells because of its insusceptibility to the ubiquitous cytoplasmic ribonuclease inhibitor, and its high stability and catalytic activity. Here, we characterized in vitro and in vivo an immunoRNase, scFv 4D5-dibarnase, which consists of two barnase molecules that are fused serially to the single-chain variable fragment (scFv) of humanized 4D5 antibody. The latter is directed against the extracellular domain of human epidermal growth factor receptor 2 (HER2), a cancer marker that is overexpressed in many human carcinomas. The scFv 4D5-dibarnase exerted a specific cytotoxic effect on HER2-overexpressing SKBR-3 and BT-474 human breast carcinoma cells (IC50=4.1 and 2.4 nM, respectively) via induction of apoptosis. Ten doses of 0.7 mg/kg scFv 4D5-dibarnase to BALB/c nude mice that bore SKBR-3 human breast cancer xenografts resulted in a 76% reduction in tumor growth. A single injection of scFv 4D5-dibarnase at a total course dose of 7 mg/kg did not cause severe side effects in BALB/c nude or BDF1 mice. The cytotoxicity and selectivity of scFv 4D5-dibarnase merit consideration of this immunoRNase as a potent anticancer agent.

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KW - Ribonuclease

KW - Toxicity

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