Nonclinical toxicology development of a novel antibody antibiotic conjugate for treating invasive Staphylococcus Aureus infections

• Published in: Toxicology and applied pharmacology Vol. 435; p. 115811
• Main Authors: Stagg, Nicola J., Katavolos, Paula, Achilles Poon, Kirsten, Zhong, Shelly, Ljumanovic, Nina, Kamath, Amrita, Cai, Hao, Carrasco-Triguero, Montserrat, Halpern, Wendy
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.01.2022
• Subjects: Administration, Intravenous; Animals; Antibiotics; Antibody-mediated delivery; Cardiovascular Diseases - chemically induced; Cell Wall - chemistry; Drug Delivery Systems; Female; Globulins - metabolism; Immunotoxins - therapeutic use; Immunotoxins - toxicity; Infectious disease; Macaca fascicularis; Male; Mutagenicity Tests; Nervous System Diseases - chemically induced; Nonclinical toxicology; Rats; Rats, Sprague-Dawley; Safety assessment; Spermatozoa - drug effects; Staphylococcal Infections - drug therapy; Staphylococcal Infections - microbiology; Staphylococcus aureus; Testis - pathology; Infectious disease; Antibiotics; Safety assessment; Staphylococcus aureus; Antibody-mediated delivery; Nonclinical toxicology
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2021.115811

Invasive Staphylococcus aureus (S. aureus) infections are a leading cause of death and not effectively treated with prolonged standard of care antibiotics. A novel THIOMAB™ antibody antibiotic conjugate (TAC) was developed that uses a bacterial-wall specific antibody to deliver the antibiotic (dmDNA31, a rifamycin analogue) to bacteria to minimize toxicities typically seen with prolonged use of traditional antibiotics. The TAC nonclinical toxicology package included repeat dose rat and cynomolgus monkey toxicology studies for 8 weekly intravenous (IV) doses, a 7-day daily repeat dose IV toxicology study of dmDNA31 and an assessment of genotoxicity, cardiovascular toxicity, neurotoxicity and sperm parameters. TAC and dmDNA31 were well tolerated in rats and monkeys, and there was no evidence of genotoxicity, cardiovascular toxicity or neurotoxicity. Non-adverse findings were observed and included blue discoloration in skin, blood, etc. due to the blue color of dmDNA31, increased globulin due to the high doses of antibodies, and abnormal sperm morphology of small heads in male rats with no histopathology correlate in testis. This is an example of antibody-mediated delivery of an antibiotic that has the potential to offer a more effective way of eradicating infection while providing a better safety profile compared to traditional antibiotics.