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 comp lement activation, whereas those containing human g4 or murine g1 anti bodies generally do not. Therefore, isotype selection of therapeutic a ntibodies 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 (mA b) (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 in vestigate whether isotype difference could influence mAb efficacy in p athological disease states, hamster/murine chimeric g1 and g2a anti-mu rine TNF-alpha mAbs (TN3g1, TN3g2a) were studied in experimental shock in mice and rats. In lipopolysaccharide-induced shock in mice, treatm ent 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 les s than or equal to 0.05), respectively, compared with 100% mortality b y 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 equa l to 0.05). In a neutropenic sepsis model in rats there was greater su rvival in animals receiving the gl isotype of TN3 compared with g2a is otype variant (70 vs. 27%; p less than or equal to 0.005) with 100% mo rtality in the controls. These differences were not due to the pharmac okinetic profiles of the mAbs. In models of experimental shock antibod y isotype can affect outcome with inactive isotypes (human g4 and muri ne g1) being more efficacious than active isotypes (human g1 and murin e g2a).