Successful therapy of collagen-induced arthritis with TNF receptor-IgG fusion protein and combination with anti-CD4.
We have previously shown that anti-tumour necrosis factor (TNF) monoclonal antibody (mAb) ameliorates established collagen-induced arthritis and that the efficacy of this form of treatment can be enhanced by concurrent anti-CD4 treatment. Here we assess the efficacy of a human p55 TNF receptor-IgG fusion protein (p55-sf2), given alone or with anti-CD4 mAb. TNF receptor-IgG fusion protein (100 micrograms) suppressed paw swelling and limb recruitment in established arthritis and reduced the incidence of erosions in the proximal interphalangeal joints from 92% to 50%, which was comparable to 41% erosions using anti-TNF mAb. Methylprednisolone acetate (4.2 mg/kg/week) reduced clinical signs of inflammation in a manner comparable to TNF blockade but had little effect on the incidence of erosions. Co-administration of anti-CD4 and TNF receptor-IgG led to an even greater therapeutic effect than TNF receptor-IgG alone, with the incidence of erosions being reduced from 100% to 17%. Serological analyses showed that the beneficial effects of anti-CD4 and TNF receptor-IgG could be partly explained by the ability of anti-CD4 to prevent a neutralizing antibody response. These results confirm the importance of TNF in destructive inflammatory arthritis and demonstrate the feasibility of therapeutically targeting TNF with a form of TNF receptor. Finally, the findings confirm the beneficial effects of TNF-targeted therapy coupled with anti-CD4 therapy.
Williams
R O
RO
Kennedy Institute of Rheumatology, London, UK.
Ghrayeb
J
J
Feldmann
M
M
Maini
R N
RN
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000917:Antibody Formation; D015703:Antigens, CD / Q000276:immunology*; D001168:Arthritis / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015704:CD4 Antigens / Q000276:immunology; D003094:Collagen / Q000276:immunology; D005552:Forelimb / Q000473:pathology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000627:therapeutic use*; D007075:Immunoglobulin M / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015704:CD4 Antigens; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011993:Recombinant Fusion Proteins; D003094:Collagen