Antibodies constitute the most rapidly growing class of human therapeutics and the second largest class of drugs after vaccines. The generation of potent antibody therapeutics, which I review here, is an iterative design process that involves the generation and optimization of antibodies to improve their clinical potential.

Potent antibody therapeutics by design

Respiratory syncytial virus (RSV) is the most frequent and important cause of lower respiratory tract infection in infants and children. It is a seasonal virus, with peak rates of infection occurring annually in the cold season in temperate climates, and in the rainy season, as temperatures fall, in tropical climates. High risk groups for severe RSV disease include infants below six mo of age, premature infants with or without chronic lung disease, infants with hemodynamically significant congenital heart disease, infants with immunodeficiency or cystic fibrosis, and infants with neuromuscular diseases. Mortality rates associated with RSV infection are generally low in previous healthy infants (below 1%), but increase significantly in children with underlying chronic conditions and comorbidities. Following early RSV lower respiratory tract infection, some patients experience recurrent episodes of wheezing mimicking early childhood asthma with persistence of lung function abnormalities until adolescence. There is currently no RSV vaccine available, but promising candidate vaccines are in development. Palivizumab, a monoclonal RSV antibody that is the only tool for immunoprophylaxis in high-risk infants, lowers the burden of RSV infection in certain carefully selected patient groups.

Burden of respiratory syncytial virus infection in young children

Properties of Human IgG1s Engineered for Enhanced Binding to the Neonatal Fc Receptor (FcRn)

BackgroundRespiratory syncytial virus (RSV) infection is associated with subsequent recurrent wheeze. Observational studies cannot determine whether RSV infection is the cause of recurrent wheeze or the first indication of preexistent pulmonary vulnerability in preterm infants. The monoclonal antibody palivizumab has shown efficacy in preventing severe RSV infection in high-risk infants. MethodsIn the double-blind, placebo-controlled MAKI trial, we randomly assigned 429 otherwise healthy preterm infants born at a gestational age of 33 to 35 weeks to receive either monthly palivizumab injections (214 infants) or placebo (215 infants) during the RSV season. The prespecified primary outcome was the total number of parent-reported wheezing days in the first year of life. Nasopharyngeal swabs were taken during respiratory episodes for viral analysis. ResultsPalivizumab treatment resulted in a relative reduction of 61% (95% confidence interval, 56 to 65) in the total number of wheezing days during the first yea...

/pdf/respiratory-syncytial-virus-and-recurrent-wheeze-in-healthy-3l4nwv5q0u.pdf

Respiratory syncytial virus and recurrent wheeze in healthy preterm infants.

Engineering the antibody Fc region to enhance the cytotoxic activity of therapeutic antibodies is currently an active area of investigation. The contribution of complement to the mechanism of action of some antibodies that target cancers and pathogens makes a compelling case for its optimization. Here we describe the generation of a series of Fc variants with enhanced ability to recruit complement. Variants enhanced the cytotoxic potency of an anti-CD20 antibody up to 23-fold against tumor cells in CDC assays, and demonstrated a correlated increase in C1q binding affinity. Complement-enhancing substitutions combined additively, and in one case synergistically, with substitutions previously engineered for improved binding to Fc gamma receptors. The engineered combinations provided a range of effector function activities, including simultaneously enhanced CDC, ADCC, and phagocytosis. Variants were also effective at boosting the effector function of antibodies targeting the antigens CD40 and CD19, in the former case enhancing CDC over 600-fold, and in the latter case imparting complement-mediated activity onto an IgG1 antibody that was otherwise incapable of it. This work expands the toolkit of modifications for generating monoclonal antibodies with improved therapeutic potential and enables the exploration of optimized synergy between Fc gamma receptors and complement pathways for the destruction of tumors and infectious pathogens.

https://www.tandfonline.com/doi/pdf/10.4161/mabs.2.2.11158

Engineered Fc variant antibodies with enhanced ability to recruit complement and mediate effector functions.

Respiratory syncytial virus (RSV) is the leading viral pathogen responsible for bronchiolitis and pneumonia in infants and young children worldwide. We have previously shown in the mouse model that treatment with an anti-RSV neutralizing monoclonal antibody (MAb) against the F glycoprotein of RSV, palivizumab, decreased lung inflammation, airway obstruction, and postmethacholine airway hyperresponsiveness. MEDI-524, or Numax, is a new MAb derived from palivizumab with enhanced neutralizing activity against RSV. We compared the effects of these two MAbs on different markers of disease severity using the murine model of RSV infection. BALB/c mice were intranasally inoculated with RSV A2. Palivizumab or MEDI-524 was administered once at either 24 h before or 48 h after RSV inoculation. Regardless of the time of administration, all treated mice showed significantly decreased RSV loads in bronchoalveolar lavage samples measured by plaque assay. Only MEDI-524 given at −24 h significantly decreased lung RSV RNA loads on days 5 and 28 after RSV inoculation. Pulmonary histopathologic scores, airway obstruction, and postmethacholine airway hyperresponsiveness were significantly reduced in mice treated with MEDI-524 at 24 h before inoculation, compared with untreated controls and the other regimens evaluated. MEDI-524 was superior to palivizumab on several outcome variables of RSV disease assessed in the mouse model: viral replication, inflammatory and clinical markers of acute disease severity, and long-term pulmonary abnormalities.

Comparative Effects of Two Neutralizing Anti-Respiratory Syncytial Virus (RSV) Monoclonal Antibodies in the RSV Murine Model: Time versus Potency

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Comparative Effects of Two Neutralizing Anti-Respiratory Syncytial Virus (RSV) Monoclonal Antibodies in the RSV Murine Model: Time versus Potency