COMPLEMENT INHIBITION BY FUT-175 AND K76-COOH IN A PIG-TO-HUMAN LUNG XENOTRANSPLANT MODEL

Two complement inhibitors, FUT-175 (FUT) and K76-COOH (K76), were stud ied as single agents in an ex vivo, in situ model of pig lung rejectio n by human blood. Pulmonary toxicity (primarily increased pulmonary va scular resistance [PVR]) was seen with FUT at a dose which inhibited c omplement in vitro (0.4 mg/ml); a lower dose (0.1 mg/ml) was therefore used. K76 had little apparent toxicity at a dose which inhibited comp lement in vitro (6 mg/ml), but activated complement, leading to C3a el aboration. Efficacy was then assessed by 1) deposition of complement p athway components in the lung and 2) lung survival during perfusion wi th human blood. Neither agent consistently prolonged median lung survi val (FUT: 50 min.+/-28 SEM; K76: 37+/-16), blocked thromboxane product ion, or prevented PVR elevation compared to experiments using unmodifi ed human blood (survival 9 min.+/-2). At the doses used, both agents p revented deposition of terminal complement complex (TCC) in the lung. This finding demonstrates that the various phenomena associated with h yperacute lung rejection (thromboxane release, PVR elevation, capillar y leak, and intraalveolar hemorrhage) can all occur despite abrogation of membrane attack complex formation. We can not exclude a contributi on by drug toxicity or complement damage (mediated by C3a or other com plement pathway components proximal to TCC) to the observed lung injur y. We conclude that, although both FUT and K76 inhibit deposition of T CC in the lung, at the dose tested neither drug is useful as a single agent to prolong survival in a pig-to-human lung xenograft model.