Chimeric anti-CD14 IGG2/4 Hybrid antibodies for therapeutic intervention in pig and human models of inflammation.
CD14 is a key recognition molecule of innate immune responses, interacting with several TLRs. TLR signaling cross-talks extensively with the complement system, and combined CD14 and complement inhibition has been proved effective in attenuating inflammatory responses. Pig models of human diseases have emerged as valuable tools to study therapeutic intervention, but suitable neutralizing Abs are rare. Undesired Fc-mediated functions, such as platelet activation and IL-8 release induced by the porcine CD14-specific clone Mil2, limit further studies. Therefore, an inert human IgG2/IgG4 hybrid C region was chosen for an rMil2. As revealed in ex vivo and in vivo pig experiments, rMil2 inhibited the CD14-mediated proinflammatory cytokine response similar to the original clone, but lacked the undesired Fc-effects, and inflammation was attenuated further by simultaneous complement inhibition. Moreover, rMil2 bound porcine FcRn, a regulator of t1/2 and biodistribution. Thus, rMil2, particularly combined with complement inhibitors, should be well suited for in vivo studies using porcine models of diseases, such as sepsis and ischemia-reperfusion injury. Similarly, the recombinant anti-human CD14 IgG2/4 Ab, r18D11, was generated with greatly reduced Fc-mediated effects and preserved inhibitory function ex vivo. Such Abs might be drug candidates for the treatment of innate immunity-mediated human diseases.
Somatic Research Center, Nordland Hospital, Bodø N-8092, Norway;
Corinna
C
Lau
Kristin S
KS
Gunnarsen
Lene S
LS
Høydahl
Jan Terje
JT
Andersen
Gøril
G
Berntzen
Anne
A
Pharo
Julie K
JK
Lindstad
Judith K
JK
Ludviksen
Ole-Lars
OL
Brekke
Andreas
A
Barratt-Due
Erik Waage
EW
Nielsen
Christopher R
CR
Stokes
Terje
T
Espevik
Inger
I
Sandlie
Tom Eirik
TE
Mollnes
D000818:Animals; D000906:Antibodies; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology / Q000627:therapeutic use; D000943:Antigens, Differentiation / Q000276:immunology; D002460:Cell Line; D003167:Complement Activation / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000627:therapeutic use*; D007167:Immunotherapy; D007249:Inflammation / Q000276:immunology* / Q000628:therapy*; D018950:Lipopolysaccharide Receptors / Q000276:immunology*; D017452:Receptors, IgG / Q000276:immunology; D034421:Sus scrofa
D000906:Antibodies; D000888:Antibodies, Anti-Idiotypic; D000943:Antigens, Differentiation; C489017:FCGR1A protein, human; D007074:Immunoglobulin G; D018950:Lipopolysaccharide Receptors; D017452:Receptors, IgG; C062010:leu-13 antigen