DIFFERENTIAL EFFECT OF ISOTYPE ON EFFICACY OF ANTITUMOR NECROSIS FACTOR-ALPHA CHIMERIC ANTIBODIES IN EXPERIMENTAL SEPTIC SHOCK

Immune complexes containing human gamma (g)1 or murine g2a antibodies generate secondary effector mechanisms via pc receptor binding or complement activation, whereas those containing human g4 or murine g1 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-alpha mcnoclonal antibody (mAb) (cCB0011) showed a dose-dependent inhibition of pyrexia, whereas a g1 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 g1 and g2a anti-murine TNF-alpha mAbs (TN3g1, TN3g2a) were studied in experimental shock in mice and rats. In lipopolysaccharide-induced shock in mice, treatment with TN3g1 mAb at 30 and 3 mg/kg resulted in 90% survival by 72 h (p less than or equal to 0.004), and prolonged survival to 45 h (p less than or equal to 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 less than or equal to 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 less than or equal to 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 g1) being more efficacious than active isotypes (human g1 and murine g2a).