The clinical application of conventional peptide drugs often is limited by their short in vivo half-life and potential immunogenicity. Frequent injection presents challenges to the treatment of chronic diseases, such as HIV infection. We chemically modified a peptide HIV fusion inhibitor with 3-maleimidopropionic acid (MPA), which allows rapid and irreversible conjugation with serum albumin at a 1:1 molar ratio. FB006M, with an MPA modification at the 13th amino acid, rapidly formed conjugate with albumin upon intravenous injection, and it exhibited a remarkably extended in vivo half-life. The albumin conjugate of FB006M displayed potent inhibitory activity against a number of laboratory and clinical isolates of HIV-1 in vitro and in vivo. No immunogenicity or antibody formation was detected after repeated dosing. The clinical application of FB006M may decrease the cost of treatment and improve treatment compliance and patient quality of life.The current treatment of HIV infection and AIDS faces the challenge of the widespread emergence of drug-resistant HIV-1 variants in both newly infected and drug-experienced patients (17). This emphasizes the need for therapeutics with new mechanisms of action. Enfuvirtide, the first and only FDA-approved HIV-1 fusion inhibitor, showed potent activity against both wild-type and drug-resistant HIV-1 (11,12). Being a peptide of 36 amino acid residues, however, it suffers from a short in vivo half-life of 3.46 to 4.35 h and requires twice-daily injection (16). To reduce the cost of treatment and improve patient quality of life, we were interested in developing a peptide-based and long-acting HIV fusion inhibitor by covalently linking an anti-HIV fusion peptide to serum albumin at a 1:1 molar ratio.Albumin is the most abundant protein in plasma. It is well distributed in different tissues and exhibits a half-life of 15 to 19 days in humans. Because of these properties, albumin has been used as a drug carrier (1,6,7). This approach has been applied to small-molecule drugs (9), peptides (10), and protein therapeutics (2). These albumin-drug conjugates demonstrated prolonged in vivo half-life, excellent safety profiles, and therapeutic efficacy. To apply this approach to peptide-based HIV-1 fusion inhibitors, we recognized three important questions that had to be addressed. First, albumin is one magnitude greater in molecular weight than the anti-fusion peptides. The linkage of albumin to peptide may prevent the peptide from accessing its target by steric hindrance (8). Therefore, the linkage site in both albumin and peptide has to be selected carefully so that the final peptide-albumin conjugate retains its biological activities. Second, the molar ratio of peptide to albumin in a conjugate can affect both activity and half-life (20). A chemical modification of peptide that allows a 1:1 molar ratio was used to assure the minimum structural alteration of albumin after peptide linkage. Third, an albumin conjugate in circulation with a long half-life may be immunogenic. It could, ther...

No abstract

The novel virucidal protein cyanovirin-N (CV-N) binds with equally high affinity to soluble forms of either H9 cell-produced or recombinant glycosylated HIV-1 gp120 (sgp120) or gp160 (sgp160). Fluorescence polarization studies showed that CV-N is also capable of binding to the glycosylated ectodomain of the HIV-envelope protein gp41 (sgp41) (as well as SIV glycoprotein 32), albeit with considerably lower affinity than the sgp120/CV-N interaction. Pretreatment of CV-N with either sgp120 or sgp41 abrogated the neutralizing activity of CV-N against intact, infectious HIV-1 virions. Isothermal calorimetry and optical biosensor binding studies showed that CV-N bound to recombinant sgp120 with a K(d) value ranging from 2 to 45 nM and to sgp41 with a K(d) value of 606 nM; furthermore, they indicated an approximate 5:1 stoichiometry for CV-N binding to sgp120 and a 1:1 stoichiometry for CV-N binding to sgp41. Circular dichroism studies additionally illuminated the binding of CV-N with both sgp120 and sgp41, providing the first direct evidence that conformational changes are a consequence of CV-N interactions with both HIV-1 envelope glycoproteins.

Mentoring during graduate training confers a multitude of benefits. However, despite these benefits, health service psychology programs (e.g., counseling and clinical psychology) could benefit from additional attention to mentoring and associated outcomes. Although the field of health service psychology has examined advising during graduate training, we argue that mentoring is often distinct from advising and encourage a deliberate switch from the traditional role of faculty advisor to a more proactive role of faculty mentor. We highlight the limited prevalence of mentoring in health service psychology doctoral programs and provide a discussion of conceptual differences in the roles and functions of an advisor and a mentor. We also note the plethora of benefits associated with mentoring relationships and discuss how these relationships are formed. Finally, we offer several recommendations to assist health service subfields of psychology in being more proactive. We hope that the field will recognize the value of mentoring during graduate training.

1 Cell-surface expression of CD40 in B-cell malignancies and multiple solid tumors has raised interest in its potential use as a target for antibody-based cancer therapy. SGN-40, a humanized monoclonal anti-CD40 antibody, mediates antibody-dependent cytotoxicity and inhibits B-cell tumor growth in vitro, properties of interest for the treatment of cancers, and is currently in Phase I clinical trials for B-cell malignancies. In this study, we determined in vivo activity and pharmacokinetics properties of SGN-40. 2 Effect of SGN-40 in xenograft model of CD40-expressing B-cell lymphoma in severe-combined immune deficiency mice and its in vivo pharmacokinetics properties in normal mice, rats and cynomolgus monkeys were studied. 3 Treatment with SGN-40 significantly increased the survival of mice xenografted with human B-cell lymphoma cell line. SGN-40 exhibited nearly 100% bioavailability in mice and it cleared faster when given at a low dose. In monkeys, clearance of SGN-40 was also much faster at low dose, suggesting nonlinear pharmacokinetics in these species. In rats, however, SGN-40 clearance at all tested doses was similar, suggesting that pharmacokinetics were linear in this dose range in rats. Administration of SGN-40 to monkeys also produced marked, dose-dependent, and persistent depletion of peripheral CD20 þ B lymphocytes. 4 Data presented in this report suggest that SGN-40 is active in in vivo, and based upon interspecies scaling, SGN-40 clearance in humans is predicted to be similar to observed SGN-40 clearance in monkeys. These data suggest that SGN-40 has appropriate pharmacokinetic properties that support its clinical use.