A chimeric anti-human tissue factor antibody attenuates inflammatory responses in rhesus monkeys challenged with E. coli

Abstract number: OC307

Zhu^* X. Y., Wang† Q. Q., Hao† P., Wong^* H. C., Jiao^* J. A.

†Kunming Medical School, Yunnan, Peoples Republic of China ^*USA;

A septic shock model was established by challenging rhesus monkeys with different doses (5 × 109–4 × 1010 CFU) of live E. coli (086:K61H). The protective effect of a chimeric anti-human tissue factor (TF) antibody, Sunol-cH36, was investigated at a lethal E. coli dose (4 × 10¹⁰ CFU). Sunol-cH36 is a unique anti-TF antibody that inhibits TF-fVIIa-dependent factor X and IX activation by specifically blocking factor X and IX binding to TF or TF-fVIIa complex. In this study, rhesus monkeys were given a bolus injection of vehicle (PBS) or Sunol-cH36 (10 mg kg^-1) 30 min prior to a 2-h infusion of lethal E. coli dose. Each animal was observed for survival times and changes in vital signs. The levels of inflammatory cytokines (TNFa, IL-1b, IL-6, and IL-8) were analyzed at T= 0–2-, 4-, and 6-h post-E. coli infusion. The mean survival times for treated and control groups were 111 and 19 h, respectively. Sunol-cH36 administration also attenuated cellular injury in lung, kidney, adrenal, brain, and small intestine. Sunol-cH36 significantly reduced the IL-1b and IL-8 produced in response to lethal dose of E. coli at T= 2, 4 and 6 h. IL-1b levels were 0, 7, and, 1 ng mL^-1 for the treated group, a decrease from 5, 17, and 6 ng mL^-1 for the control group. IL-8 levels decreased from 21, 26, and 40 ng mL^-1 for the control group to 12, 3, and 4 ng mL^-1 for the treated group. The effect of Sunol-cH36 on TNFa and IL-6 was less significant. Treatment with Sunol-cH36 did not increase bleeding events. It was concluded that Sunol-cH36 attenuates inflammatory responses to lethal dose of E. coli and prolongs the survival times of rhesus monkeys with E. coli-induced septic shock. This is comparable to the previous observations that blocking the interaction between TF and factor VII or VIIa by an anti-TF antibody or by active site-inhibited factor VIIa prevented or attenuated lethal E. coli septic shock in baboons.

1  Taylor, FB, Jr et al. 1991 Circulatory Shock 33: 127–134.

2  Taylor, FB, Jr et al. 1998 Blood 91: 1609–1615.