Generation and Improvement of Effector Function of a Novel Broadly Reactive and Protective Monoclonal Antibody against Pneumococcal Surface Protein A of Streptococcus pneumoniae

PLoS One. 2016 May 12;11(5):e0154616. doi: 10.1371/journal.pone.0154616. eCollection 2016.

Abstract

A proof-of-concept study evaluating the potential of Streptococcus pneumoniae Pneumococcal Surface Protein A (PspA) as a passive immunization target was conducted. We describe the generation and isolation of several broadly reactive mouse anti-PspA monoclonal antibodies (mAbs). MAb 140H1 displayed (i) 98% strain coverage, (ii) activity in complement deposition and opsonophagocytic killing (OPK) assays, which are thought to predict the in vivo efficacy of anti-pneumococcal mAbs, (iii) efficacy in mouse sepsis models both alone and in combination with standard-of-care antibiotics, and (iv) therapeutic activity in a mouse pneumonia model. Moreover, we demonstrate that antibody engineering can significantly enhance anti-PspA mAb effector function. We believe that PspA has promising potential as a target for the therapy of invasive pneumococcal disease by mAbs, which could be used alone or in conjunction with standard-of-care antibiotics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / immunology*
  • Antibodies, Monoclonal / therapeutic use
  • Bacterial Proteins / immunology*
  • Complement C3 / metabolism
  • Disease Models, Animal
  • Epitope Mapping
  • Female
  • Humans
  • Immunoglobulin G / blood
  • Lung Diseases / immunology
  • Lung Diseases / microbiology
  • Mice, Inbred BALB C
  • Opsonin Proteins / metabolism
  • Phagocytes / metabolism
  • Phagocytosis
  • Pneumococcal Infections / drug therapy
  • Pneumococcal Infections / immunology
  • Pneumococcal Infections / microbiology
  • Protein Binding
  • Sepsis / drug therapy
  • Sepsis / immunology
  • Sepsis / microbiology
  • Streptococcus pneumoniae / immunology*
  • Treatment Outcome

Substances

  • Anti-Bacterial Agents
  • Antibodies, Monoclonal
  • Bacterial Proteins
  • Complement C3
  • Immunoglobulin G
  • Opsonin Proteins
  • pneumococcal surface protein A

Grants and funding

This work was supported by Kyowa Hakko Kirin Co., Ltd. Japan (http://www.kyowakirin.com/index.html). All named authors are or were employees of Kyowa Kirin Pharmaceutical Research, Inc. or Kyowa Hakko Kirin Co., Ltd., Japan at the time of their involvement in the reported study. Kyowa Hakko Kirin Co., Ltd., Japan provided funding for the research of the study and provided support in the form of salaries for authors SK, TO, SB, RC, BG, TK, GD, JL, LK, TT, and YK, but no individuals employed by the funder, other than the named authors, had any additional role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.