Antitumor activity and toxicity of anti-HER2 immunoRNase scFv 4D5-dibarnase in mice bearing human breast cancer xenografts.
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 (IC(50) = 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.
Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya, 16/10, Moscow, 117997, Russia. taras.b@mail.ru
Taras G
TG
Balandin
Evelina
E
Edelweiss
Natalia V
NV
Andronova
Elena M
EM
Treshalina
Alexander M
AM
Sapozhnikov
Sergey M
SM
Deyev
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001426:Bacterial Proteins; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D051379:Mice; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*; D012260:Ribonucleases / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*; D057127:Single-Chain Antibodies / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D012260:Ribonucleases; D057127:Single-Chain Antibodies; C557290:immunoRNase scFv 4D5-dibarnase; C019760:Bacillus amyloliquefaciens ribonuclease