Differential Effect o f Isotype on Efficacy o f Anti - Tumor Necrosis Factor c ~ Chimeric Antibodies in Experimental Septic Shock

Immune complexes containing human gamma (g)l or murine g2a antibodies generate secondary erector mechanisms via Fc receptor binding or complement activation, whereas those containing human g4 or murine gl antibodies generally do not. Therefore, isotype selection of therapeutic antibodies may have important clinical consequences. In a rabbit model of recombinant human tumor necrosis factor (rhuTNF)-induced pyrexia, a murine/human chimeric g4 anti-human TNF-ot mcnoclonal antibody (mAb) (cCB0011) showed a dose-dependent inhibition ofpyrexia, whereas a gl isotype variant of the same mAb gave a marked pyrexia that was seen at all doses indicative of an immune complex-mediated response. To investigate whether isotype difference could influence mAb efficacy in pathological disease states, hamster/murine chimeric gl and g2a anti-murine TNF-o~ mAbs (TN3gl, TN3g2a) were studied in experimental shock in mice and rats. In lipopolysaccharide-induced shock in mice, treatment with TN3gl mAb at 30 and 3 mg/kg resulted in 90% survival by 72 h 00 ~< 0.004), and prolonged survival to 45 h (p ~< 0.05), respectively, compared with 100% mortality by 27 h in controls. In contrast, a g2a isotype variant of the same mAb (30 mg/kg) resulted in only 10% survival by 72 h (p ~< 0.05). In a neutropenic sepsis model in rats there was greater survival in animals receiving the gl isotype of TN3 compared with g2a isotype variant (70 vs. 27%; p ~< 0.005) with 100% mortality in the controls. These differences were not due to the pharmacokinetic profiles of the mAbs. In models of experimental shock antibody isotype can affect outcome with inactive isotypes (human g4 and murine gl) being more efficacious than active isotypes (human gl and murine g2a).