CD28 Homodimer Interface Mimetic Peptide Acts as a Preventive and Therapeutic Agent in Models of Severe Bacterial Sepsis and Gram-Negative Bacterial Peritonitis

Severe gram-negative bacterial infections, including sepsis, are a major cause of morbidity and mortality worldwide [1]. Despite the availability of potent antimicrobial agents and advances in supportive care, mortality from sepsis has persisted at >20% [2]. Consequently, there have been concerted efforts to develop agents that can either neutralize bacterial virulence factors and/or enhance host defenses that, in conjunction with antibiotic therapy, may improve the outcome from these infections. Optimal T-cell responses require not only an interaction between the T-cell receptor (TCR) and major histocompatibility complex class II on antigen-presenting cells (APCs), but also costimulatory signaling through CD28 expressed on the T cell and B-7 coligands (CD80 and CD86) on APCs. We developed a novel, host-oriented therapeutic approach to provide broad protection against gram-positive bacteria and their exotoxins in which peptides target CD28, the principal human costimulatory receptor, to prevent the excessive, harmful inflammatory cytokine response underlying infection pathology [3, 4]. AB103 (previously known as p2TA) is an octapeptide derived from the homodimer interface of CD28, which is essential for the induction of many proinflammatory cytokines, that attenuates signaling through CD28 [3]. CD28 also functions as a critical superantigen receptor [3, 4]. AB103/p2TA blocks not only superantigen-mediated lethality in mice, but also lethal group A Streptococcus pyogenes infection [3, 5]. The finding that AB103 attenuates the inflammatory immune response to gram-positive bacterial infection [5] suggested that the peptide might be capable of intervening also with downstream signaling of CD28 in cases of severe bacterial infection that are not directly mediated by superantigens. Recent evidence indicates that blockade of costimulatory signals, including CD40 and/or CD80/86, might reduce mortality in experimental intra-abdominal sepsis [6]. We therefore tested the ability of this CD28 mimetic peptide to protect mice from lethal experimental sepsis. We now demonstrate that AB103 potently reduces the induction of tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) by lipopolysaccharide (LPS) in human peripheral blood mononuclear cells (PBMCs) and protects mice from lethality following intraperitoneal LPS or gram-negative bacterial challenges, as well as in the cecal ligation/puncture (CLP) model of polymicrobial sepsis.