Anti-endotoxin therapy in primate bacteremia with HA-1A and BPI.
OBJECTIVE
The in vivo neutralizing activities of an anti-lipopolysaccharide (LPS) antibody HA-1A (Centoxin [Centocor, Malvern, PA]), a human immunoglobulin M monoclonal antibody, and of bactericidal/permeability-increasing protein (BPI), an endogenously produced human LPS-neutralizing protein, were studied in a primate model of lethal Escherichia coli bacteremia.


BACKGROUND
HA-1A has been used with variable success against LPS activity in some animal models and in a recently reported clinical trial. However, no data assessing the efficacy of this agent in subhuman primates is available. Bactericidal/permeability-increasing protein is a product of polymorphomononuclear cells (PMNs) that is stored in azurophilic granules and exhibits LPS-neutralizing activity in vitro and in some in vivo models.


METHODS
Immediately after E. coli infusion and in a blinded fashion, three baboons were treated with BPI (5 mg/kg bolus infusion and 95 micrograms/kg/min infusion over 4 hr). Three animals received 3 mg/kg BW of HA-1A, whereas another three baboons received a placebo treatment.


RESULTS
The BPI-treated animals demonstrated significantly (p < 0.03) lower circulating LPS-limulus amoebocyte lysate (LAL) activity compared with the control animals, but this reduction in LPS-LAL activity was not associated with improved survival. HA-1A treatment did not reduce LPS-LAL activity. However, both BPI and HA-1A treatment did attenuate the pro-inflammatory cytokine response.


CONCLUSIONS
The current data suggests that incomplete neutralization of endotoxin activity does not alter mortality from severe bacteremia. Given the diversity of mediator production under such circumstances, a strategy of combination therapy in the form of anti-lipopolysaccharide and anticytokine treatment may be necessary to achieve optimal survival.
Department of Surgery, New York Hospital-Cornell University Medical College, New York.
M A
MA
Rogy
L L
LL
Moldawer
H S
HS
Oldenburg
W A
WA
Thompson
W J
WJ
Montegut
S A
SA
Stackpole
A
A
Kumar
M A
MA
Palladino
M N
MN
Marra
S F
SF
Lowry
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D016470:Bacteremia / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000503:physiopathology / Q000628:therapy*; D001798:Blood Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D004731:Endotoxins / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D004927:Escherichia coli Infections / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D006439:Hemodynamics / Q000187:drug effects; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008033:Limulus Test; D008070:Lipopolysaccharides / Q000097:blood; D008969:Molecular Sequence Data; D010215:Papio; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D012795:Sialoglycoproteins / Q000187:drug effects / Q000378:metabolism; D015996:Survival Rate; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001798:Blood Proteins; D004731:Endotoxins; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; C068069:nebacumab