Inactivation of CD59 as a therapeutic strategy

Develop therapeutic approaches for diseases such as cancer and viral infections that exploit endogenous CD59 to evade the host immune system. In these diseases, inhibiting CD59 activity could potentiate immune-mediated lysis.

Capitalize on the unique properties of the intermedilysin (ILY) toxin secreted by a pathogeneic Streptococcus strain  to develop novel therapeutic modalities for treating diseases, such as cancer and viral infection, that would benefit from stimulation of the immune system. This phenomenon has been exploited to develop a powerful genetic-based method for destroying specific cell types in transgenic mice, and is being explored for therapeutic use in humans.

Exploit the conditional, targeted, cell ablation methodology in transgenic mice to develop commercial products for use in laboratory research, as well as in industrial preclinical studies, focused on the mechanism of action and toxicology for drug candidates. 

The ubiquitously expressed cell surface protein CD59 is a negative regulator of the complement cascade, and certain cancer cells and enveloped viruses incorporate or over-express CD59 in order to escape complement-dependent cytotoxicity (CDC). Inhibiting CD59 restores sensitivity to CDC, and Dr. Qin is:

• Continuing investigations into the complement-dependent and complement-independent activities of CD59, using a combination of mouse genetics and biochemical approaches, to gain insights into the regulation of the complement system.
   
• Defining the roles of CD59 and MAC in the pathogenesis of human diseases such as hemolytic anemia, platelet activation, and atherosclerosis
   
• Expanding the research applications of the ILY/human CD59 binding in transgenic mice for targeting and destroying specific cell types.
   
• Investigating biochemical aspects of ILY binding to human CD59.
   
• Exploring the therapeutic potential derived from ILY’s binding selectivity and potent affinity for human CD59, in the context of modulating the complement activation cascade.

Dr. Qin’s group in the Laboratory for Translational Research (LTR) has been unraveling the cascade of biochemical reactions underlying the complement system, which plays a crucial role in both acquired and innate immune responses. Dr. Qin’s major focus is on the GPI-linked complement regulatory protein, CD59. This protein serves to block a key step in the terminal phase of complement activation, namely the formation of the membrane attack complex (MAC). The MAC is responsible for lysing the target cell harboring a foreign antigen, but is prevented from lysing “self” tissues by negative regulators, such as CD59. Dr. Qin has generated mCD59 knockouts and human CD59 transgenic mice, investigating the role of CD59 in atherosclerosis and sperm and erythrocyte functions.

Biological Mechanisms and Pathways

• CD59 •
• Complement •
• Complement-mediated immune reaction •
• GPI-linked membrane protein •
• Immunity •
• Immunology •
• Intermedilysin •
• Membrane attack complex •
• Membrane permeability •
• Oncology
•  

Cancer

• Cancer •
• Intermedilysin •
• Oncology
•  

Disease Mechanisms

• Cancer •
• HIV •
• Parasites •
• Pathogen •
• Viral infection
•  

Immunology

• Immunology
•  

Infectious Disease

• CMV •
• HIV •
• Parasites •
• Parasites •
• Pathogen •
• Pathogen
•  

Research Tools and Instrumentation

• Conditional targeted cell ablation •
• Transgenic mice
•  

Therapeutic Discovery Tools and Assays

• Cancer
•  

Therapeutics

• Anti-bacterial therapy •
• Conditional targeted cell ablation •
• Intermedilysin
•