Lead Candidate

Monoclonal antibodies directed Against Sepsis

Sepsis results from a dysregulated immune response to infection, leading to widespread inflammation, organ dysfunction, and potentially death. Despite medical advancements, sepsis continues to be a leading cause of mortality globally. Its pathophysiology involves bacterial endotoxins from Gram-negative bacteria (e.g., LPS) and exotoxins from Gram-positive bacteria (e.g., LTA and PGN), which overstimulate the immune system and cause septic shock.

Monoclonal antibodies offer a promising approach to targeting specific pathogens and neutralizing toxins. Longhorn is developing a cocktail containing antibodies against multiple bacterial antigens could provide broad-spectrum protection against sepsis. This approach and the targets identified, build on the over four decades of experience the Longhorn management team has had developing antibody treatments for the prevention and treatment of bacterial infections.

Rationale for a Multivalent Approach

1. Diversity of Bacterial Pathogens: Sepsis is caused by both Gram-positive and Gram-negative bacteria. A cocktail of antibodies targeting multiple bacterial antigens can offer broad-spectrum protection.

2. Neutralization of Toxins:

• Anti-LTA Antibodies: Lipoteichoic acid, a major Gram-positive bacterial cell wall component, induces inflammation. Anti-LTA antibodies can block this interaction with immune receptors, preventing harmful immune activation.

• Anti-PGN Antibodies: Peptidoglycan, another Gram-positive cell wall component, triggers inflammation and immune activation. Anti-PGN antibodies can reduce inflammation and enhance bacterial clearance.

• Anti-LPS Antibodies: LPS is a potent endotoxin found in the outer membrane of Gram-negative bacteria. Neutralizing anti-LPS antibodies reduce its inflammatory effects, mitigating the severity of septic shock.

1. Opsonization and Bacterial Clearance: The antibody cocktail can opsonize both Gram-positive and Gram-negative bacteria, facilitating their recognition and clearance by immune cells.

2. Complement Activation: The antibodies can activate the complement system, directly leading to bacterial cell lysis.

Potential Benefits of the Antibody Cocktail

1. Rapid Action: The antibody cocktail can quickly neutralize bacterial toxins and enhance pathogen clearance, potentially preventing sepsis progression.

2. Prophylactic Use: High-risk patients, such as those post-surgery or immunocompromised, could receive the cocktail to prevent sepsis development.

3. Reduced Antibiotic Use: It can help reduce reliance on antibiotics, thus slowing the development of antibiotic resistance.

4. Combination Therapy: It can be used alongside existing antibiotics, enhancing overall treatment effectiveness.

Conclusion

A monoclonal antibody cocktail targeting LTA, PGN, and LPS offers a comprehensive and innovative strategy for sepsis treatment and prevention. By neutralizing key toxins and enhancing bacterial clearance, this cocktail can significantly improve patient outcomes and reduce sepsis mortality. Further research is needed to establish the safety, efficacy, and optimal clinical application of this promising approach.