TNT003, an inhibitor of the serine protease C1s, prevents complement activation induced by cold agglutinins.
Activation of the classical pathway (CP) of complement is often associated with autoimmune disorders in which disease pathology is linked to the presence of an autoantibody. One such disorder is cold agglutinin disease (CAD), an autoimmune hemolytic anemia in which autoantibodies (cold agglutinins) bind to red blood cells (RBCs) at low temperatures. Anemia occurs as a result of autoantibody-mediated CP activation on the surface of the erythrocyte, leading to the deposition of complement opsonins that drive extravascular hemolysis in the liver. Here we test the effects of TNT003, a mouse monoclonal antibody targeting the CP-specific serine protease C1s, on CP activity induced by cold agglutinins on human RBCs. We collected 40 individual CAD patient samples and showed that TNT003 prevented cold agglutinin-mediated deposition of complement opsonins that promote phagocytosis of RBCs. Furthermore, we show that by preventing CP activation, TNT003 also prevents cold agglutinin-driven generation of anaphylatoxins. Finally, we provide evidence that CP activity in CAD patients terminates prior to activation of the terminal cascade, supporting the hypothesis that the primary route of RBC destruction in these patients occurs via extravascular hemolysis. Our results support the development of a CP inhibitor for the treatment of CAD.
True North Therapeutics, Inc., South San Francisco, CA.
Ju
J
Shi
True North Therapeutics, Inc., South San Francisco, CA.
Eileen L
EL
Rose
True North Therapeutics, Inc., South San Francisco, CA.
Andrew
A
Singh
True North Therapeutics, Inc., South San Francisco, CA.
Sami
S
Hussain
True North Therapeutics, Inc., South San Francisco, CA.
Nancy E
NE
Stagliano
True North Therapeutics, Inc., South San Francisco, CA.
Graham C
GC
Parry
True North Therapeutics, Inc., South San Francisco, CA.
Sandip
http://orcid.org/0000-0001-7901-2730
S
Panicker
D000368:Aged; D000706:Anaphylatoxins / Q000378:metabolism; D000744:Anemia, Hemolytic, Autoimmune / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003167:Complement Activation / Q000187:drug effects*; D003173:Complement C1s / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D057057:Serine Proteases / Q000097:blood*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*
D000706:Anaphylatoxins; D058846:Antibodies, Monoclonal, Murine-Derived; D015842:Serine Proteinase Inhibitors; D057057:Serine Proteases; D003173:Complement C1s