Protein engineering to target complement evasion in cancer.
The complement system is composed of soluble factors in plasma that enhance or "complement" immune-mediated killing through innate and adaptive mechanisms. Activation of complement causes recruitment of immune cells; opsonization of coated cells; and direct killing of affected cells through a membrane attack complex (MAC). Tumor cells up-regulate complement inhibitory factors - one of several strategies to evade the immune system. In many cases as the tumor progresses, dramatic increases in complement inhibitory factors are found on these cells. This review focuses on the classic complement pathway and the role of major complement inhibitory factors in cancer immune evasion as well as on how current protein engineering efforts are being employed to increase complement fixing or to reverse complement resistance leading to better therapeutic outcomes in oncology. Strategies discussed include engineering of antibodies to enhance complement fixation, antibodies that neutralize complement inhibitory proteins as well as engineered constructs that specifically target inhibition of the complement system.
PAI Life Sciences Inc., Seattle, WA, United States; Compliment Corp., Seattle, WA, United States. Electronic address: darrick.carter@pailifesciences.com.
Darrick
D
Carter
Department of Medicine, University of Washington, Seattle, WA, United States.
André
A
Lieber
D000818:Animals; D003165:Complement System Proteins / Q000276:immunology*; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D015202:Protein Engineering / Q000379:methods*; D057170:Translational Research, Biomedical; D019139:Tumor Escape
D003165:Complement System Proteins
CD46; CD55; CD59; Complement inhibition; Tumor immune evasion