Charles B. Davis

Therapeutic immunization against Mycobacterium tuberculosis is an effective adjunct to antibiotic treatment.

BACKGROUND Recent advances in rational adjuvant design and antigen selection have enabled a new generation of vaccines with potential to treat and prevent infectious disease. The aim of this study was to assess whether therapeutic immunization could impact the course of Mycobacterium tuberculosis infection with use of a candidate tuberculosis vaccine antigen, ID93, formulated in a synthetic nanoemulsion adjuvant, GLA-SE, administered in combination with existing first-line chemotherapeutics rifampicin and isoniazid. METHODS We used a mouse model of fatal tuberculosis and the established cynomolgus monkey model to design an immuno-chemotherapeutic strategy to increase long-term survival and reduce bacterial burden, compared with standard antibiotic chemotherapy alone. RESULTS This combined approach induced robust and durable pluripotent antigen-specific T helper-1-type immune responses, decreased bacterial burden, reduced the duration of conventional chemotherapy required for survival, and decreased M. tuberculosis-induced lung pathology, compared with chemotherapy alone. CONCLUSIONS These results demonstrate the ability of therapeutic immunization to significantly enhance the efficacy of chemotherapy against tuberculosis and other infectious diseases, with implications for treatment duration, patient compliance, and more optimal resource allocation.

Accumulation of Antibody-Target Complexes and the Pharmacodynamics of Clotting after Single Intravenous Administration of Humanized Anti-Factor IX Monoclonal Antibody to Rats

SB-249417, a humanized monoclonal antibody (Mab) specific for the Gla domain of Factor IX, inhibits activation of this zymogen and blocks the activity of Factor IXa on Factor X, the subsequent enzyme in the clotting cascade. In the present study, the pharmacokinetics and pharmacodynamics of SB-249417 were investigated in male Sprague-Dawley rats after IV administration of single doses of 10, 50, or 250 mg/kg. Blood samples were collected for up to six weeks to assess total plasma Mab concentration and activated partial thromboplastin time (aPTT). A PK/PD model was developed using an empirical relationship between aPTT and the concentration of free Factor IX (inhibitory Emax model). The model assumed natural synthesis and degradation of the endogenous zymogen that was interrupted by the complexation of Factor IX with the antibody. Following antibody administration, aPTT values increased 5-fold above baseline at the earliest sampling time in all dose groups. Higher doses led to a longer duration of prolonge...

Subcutaneous bioavailability of a PRIMATIZEDTM IgG1 Anti-Human CD4 monoclonal antibody is dose dependent in transgenic mice bearing human CD4

IDEC-CE9.1/SB-210396 is a macaque/human chimeric IgG1 monoclonal antibody (mAb) directed against the human T-cell surface marker, CD4. This antibody has been evaluated as a potential treatment for rheumatoid arthritis and asthma, in which T cell activation is believed to play an important role in orchestrating inflammation and tissue damage. Human CD4+ murine CD4 knock-out transgenic mice (HuCD4+) have proven most useful in studying the pharmacology of CE9.1, since this antibody cross-reacts only with chimpanzee CD4 and the disposition of the antibody is highly dependent on the presence and distribution of human CD4. In the present study, the distribution and pharmacokinetics of [(3)H]CE9.1 were investigated after subcutaneous (sc) administration to HuCD4+ and murine CD4 knock-out (CD4-) transgenic mice (doses of 0.4 and 100 mg/kg). After a low sc dose to HuCD4+ mice, no absorption of CE9.1 into the systemic circulation was observed. By contrast, high systemic exposure was noted following a comparable sc dose to CD4- mice. Based on evidence that absorption of large proteins occurs primarily via the lymphatics (Supersaxo et al., Pharm. Res. 7:167, 1990), it is proposed that specific binding of CE9.1 to the CD4 molecule on lymphocytes in the regional lymph node(s) prevented the mAb from entering the systemic circulation. Saturation of CD4 binding following a high sc dose to HuCD4+ mice resulted in systemic exposure comparable to that observed at lower doses in CD4- mice. Furthermore, absorption of a low sc dose of [(3)H]CE9.1 was increased 30-fold by administration 7 h earlier of a high sc dose of unlabeled CE 9.1.

Impact of Erythrocyte Duffy Antigen Genetic Polymorphism on the Distribution of GroB-T, a Novel Human CXC Chemokine

PURPOSE Grobeta-T, a human CXC chemokine, has been studied for its potential to mobilize stem cells. Chemokines bind specifically to receptors on target immune cells but also to a homologous erythrocyte blood group antigen, the Duffy Antigen/Receptor for Chemokines (DARC)that is subject to genetic polymorphism in humans.A mutation in the DARC gene is common among African Americans and results in lack of expression of the erythrocyte antigen. We used a combination of in vitro studies of Grobeta-DARC interaction and pharmacokinetic simulation to anticipate the potential impact of this polymorphism on the pharmacokinetics of Grobeta-T. METHODS [125I]Grobeta-T was incubated in Caucasian blood to characterize the concentration dependence of the blood to plasma concentration ratio (B/P). Affinity and capacity of binding was estimated by Scatchard analysis; specificity was investigated by competitive displacement with a CC chemokine. The B/P value (7 nM) was then determined in blood from 8 African American subjects. Duffy antigen expression was determined by antibody agglutination. A pharmacokinetic model was developed which accounted for blood-cell binding. Simulations were performed to explore effects of dose regimen and DARC expression on the Grobeta-T plasma concentration-time profile. RESULTS Grobeta-T affinity and capacity for DARC (Caucasian blood)were 23.0 +/- 1.2 and 37.7 +/- 0.6 nM, respectively;excess CC chemokine fully displaced [125I]Grobeta-T. Chemokine binding was highly correlated with the presence or absence of the Duffy antigen (p<0.01) in African American blood; the proportion of subjects for which binding was observed (3/8), was consistent with the reported frequency of DARC expression in this population. Counter to intuition,in the terminal disposition phase at low doses,concentrations of free Grobeta-T in the presence of DARC may be substantially higher than in the absence of DARC. CONCLUSION Dissociation from the erythrocyte antigen may lead to greater persistence, at low doses, of free Grobetabeta-T in the blood of individuals expressing the chemokine sink.