Staurus is developing novel Fc variant humanized antibodies for the treatment and prevention of S. aureus infections. Our Fc engineering approach targets the microbial immune evasion mechanisms used by the bacterium to circumvent the host humoral immune response. S. aureus immune evasion mediators include the Immunoglobulin Fc Binding Proteins (FcBPs), which comprises Protein A (Spa), Staphylococcal Binder of Ig (Sbi) and Staphylococcal Superantigen-Like Proteins 7 and 10 (SLL7 and SLL10). S.aureus IgBPs sequester host IgGs by binding to their Fc domain, and impair their ability to engage elements of the host immune system via their Fc domains. Staurus Fc variant antibodies prevent interaction ofS.auerus IgBPs with the Fc domain, allowing the variant antibodies to retain full effector function. We believe this will translate into therapeutic antibodies with high efficacy.
Staurus’ first antibody-based biologic target is one of the most serious gram-positive organisms Staphylococcus aureus (S. aureus). Colonizing ~30% of individuals at any given time, S. aureus produces skin and soft tissue infections, wound infections, endocarditis, pneumonia, septic arthritis, osteomyelitis, foreign-body infections, and sepsis. Highly drug-resistant strains of methicillin-resistant S. aureus (MRSA) such as the USA300 clone are epidemic in both hospital and community settings. Recently, strains have shown increased tolerance or resistance in recent years to Vancomycin, Linezolid and Daptomycin with the accompanying reduction in clinical antimicrobial efficacy. Thus development of novel therapeutic agents without cross-resistance to current antimicrobials against MRSA infections is desperately needed. The capacity of S. aureus to produce such a wide array of serious and sometimes life-threatening infections reflects the diverse abilities of this pathogen to subvert clearance by the innate and adaptive immune systems of the host, including complement factors, antibodies and phagocytic cells (e.g. neutrophils and macrophages). Humans do not develop protective immunity to S. aureus despite frequent natural exposures, and all clinical trials of active vaccination or therapeutic antibody vs. S. aureus to date have failed to reach their target endpoints.
The most abundant protein on the S. aureus surface (present on 100% of strains) is the surface anchored staphylococcal Protein A (SpA). SpA tightly binds the Fc domain of host immunoglobulins (Ig). Antibodies are bound “backwards”, thus capturing and inactivating the Fc. SpA binding prevents the Ig Fc domain from carrying out its effector functions by fixing and activating complement or engaging Fc receptors on phagocytic cells to promote opsonophagocytic clearance. One could justifiably argue that all vaccine or therapeutic antibody approaches to S. aureus are ultimately doomed to fail unless the FcBP virulence mechanism is overcome.
Since the founding of Staurus, Dr. Lydon has developed a new way to counteract the FcBP virulence mechanisms, paving the way to a new generation of Fc variant therapeutic monoclonal antibody (mAb) against S. aureus. Through understanding the key virulence mechanisms of S. aureus, he developed and patented an approach to create Fc variant humanized mAbs, in which the Fc domains have been modified to prevent S.aureus FcBPs (including SpA Sbi and SSL10).
The first mAb product targets a repeat domain of SpA itself. SpA is part of the S. aureus core genome and is expressed in all sequenced strains. The SpA Ig-binding domain is repeated 4-5 times, ensuring that Staurus anti-SpA therapeutic variant mAbs will have the advantage of high avidity and increased resistance to escape mutations within the binding epitope. Targeted neutralization of SpA with a Fc variant humanized mAb will also reverses suppression of normal host immune clearance mechanisms by neutralizing the B cell super antigen activity of SpA. Preclinical studies have shown that the Fc domains of these variant antibodies do not bind to S. aureus immune evasion proteins including SpA, Sbi and SSL10. Most importantly we have demonstrated in academic labs that these mAbs indeed completely resist SpA binding, but maintain their ability to bind and activate complement factors C1q and C3b, and promote opsonophagocytic killing by human neutrophils - properties absent in the parent mAb without the unique Fc modification. In addition, targeted framework modification of the variable domain of VH3 derived antibodies prevents the superantigen binding of SpA to such antibodies. All of these points provide true advantages in developing an effective prophylactic/therapeutic approach to S. aureus infection.
· Immunoglobulins and variants directed against pathogenic microbes
US Patent 14,312,585, filed 06/23/2014