Progress Towards Recombinant Anti-Infective Antibodies

Abstract

The global market for monoclonal antibody therapeutics reached a total of $11.2 billion in 2004, with an impressive 42% growth rate over the previous five years and is expected to reach ~$34 billion by 2010. Coupled with this growth are stream-lined product development, production scale-up and regulatory approval processes for the highly conserved antibody structure. While only one of the 21 current FDA-approved antibodies, and one of the 38 products in advanced clinical trials target infectious diseases, there is increasing academic, government and commercial interest in this area. Synagis, an antibody neutralizing respiratory syncitial virus (RSV), garnered impressive sales of $1.1 billion in 2006 in spite of its high cost and undocumented effects on viral titres in human patients. The success of anti-RSV passive immunization has motivated the continued development of antiinfectives to treat a number of other infectious diseases, including those mediated by viruses, toxins and bacterial/fungal cells. Concurrently, advances in antibody technology suggest that cocktails of several monoclonal antibodies with unique epitope specificity or single monoclonal antibodies with broad serotype specificity may be the most successful format. Recent patents and patent applications in these areas will be discussed as predictors of future anti-infective therapeutics.

Two Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Studies To Investigate the Safety, Tolerability, and Pharmacokinetics of an Anti-Influenza A Virus Monoclonal Antibody, MHAA4549A, in Healthy Volunteers

“…The discovery of antibodies to protect against bacteria and toxins dates back to the early 1890s and eventually led to "serum therapy" (13,(19)(20)(21), a polyclonal antibody admixture from immunized animals or immune human donors. However, serum therapy caused a series of adverse reactions, including hypersensitivity and serum sickness, an antigen-antibody complex disease.…”

“…However, serum therapy caused a series of adverse reactions, including hypersensitivity and serum sickness, an antigen-antibody complex disease. Once antibiotics and antivirals were introduced, serum therapy lost popularity due to product batch heterogeneity, pathogen transmission, and immunogenicity risks (19,20,(22)(23)(24). In contrast, MHAA4549A is a monoclonal antibody, and in the absence of influenza virus infection, its epitope on the human influenza A virus hemagglutinin glycoprotein is not endogenously expressed in humans; therefore it is expected to be safe (7,19).…”

“…In a nonclinical study where mice were infected with a high, lethal dose of the influenza virus A/Puerto Rico/8/34 (PR8) variant and treated with subefficacious doses of MHAA4549A, the neuraminidase inhibitor oseltamivir, or a combination of the two therapies at 72 h postinfection, the combination of MHAA4549A with oseltamivir significantly improved survival and body weight over results with either treatment alone (7). Since MHAA4549A is unlikely to interact with other influenza virus antivirals, such as neuraminidase inhibitors, combination therapy allows for a dual mechanism of action and may have added benefit in hospitalized patients with severe influenza (7,13,19,20,25,28).…”

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Study To Investigate the Safety, Tolerability, and Pharmacokinetics of an Anti-Influenza B Virus Monoclonal Antibody, MHAB5553A, in Healthy Volunteers

“…Subefficacious doses of MHAB5553A together with a standard dose of oseltamivir phosphate protected more mice against mortality than oseltamivir alone in lethal influenza B infections (23). These results indicate that a combination therapy using neuraminidase inhibitors and anti-influenza B virus antibodies may hold promise as a treatment for patients hospitalized with severe influenza B infection (34)(35)(36)(37)(38). Since MHAB5553A is a monoclonal antibody, it is metabolized through catabolic pathways, unlike small-molecule neuraminidase inhibitors.…”

Opportunities and Challenges of Therapeutic Monoclonal Antibodies as Medical Countermeasures for Biodefense

“…For example, antibodies may be developed against novel targets, such as those that regulate microbial growth and virulence factor expression, or are used by a subset of microbes to infect host cells [54,55]. To fight multiple drug resistance bacteria, some successful approaches have targeted the cellular efflux pumps responsible for antibiotic resistance [56].…”