No abstract

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...

Relapse is a common cause of failure in patients with B-cell acute lymphoblastic leukaemia (B-ALL) after haploidentical haematopoietic stem cell transplantation (haplo-HSCT), and non-responders to donor lymphoblastic infusion after HSCT have a very poor prognosis. Although donor-derived CD19-directed chimeric antigen receptor-modified (CAR) T cells can potentially cure leukaemia, their effectiveness and safety have not been confirmed in relapsed B-ALL cases after haplo-HSCT. Between January 2015 and January 2017, two and four patients each received one and two infusions of CAR T cells from haplo-HSCT donors. Five (83·33%) achieved minimal residual disease (MRD)-negative remission; one patient was discharged automatically without evaluation after developing severe thrombotic microangiopathies. Four of five responsive patients relapsed after 2-7 months, and one died of sepsis following MRD-negative remission after a second infusion. None of the other second infusion recipients achieved a second complete remission. Five patients (83·33%) experienced eight courses of grade 1-3 cytokine release syndrome; two were treated with tocilizumab. Two (33·3%) and one patient developed grade 2 and 3 acute graft-versus-host disease (aGVHD), respectively; the former was controlled with glucocorticoids. Donor-derived CAR T-cell infusion seems be effective and safe for relapsed B-ALL after haplo-HSCT, although larger clinical studies are needed.

No abstract

No abstract