PRO 140, a monoclonal antibody targeting CCR5, as a long-acting, single-agent maintenance therapy for HIV-1 infection.

Background PRO 140 is a humanized monoclonal antibody targeting CCR5 with potent antiviral activity in patients with CCR5-tropic HIV-1 infection. In phase 2b studies, we evaluated the long-term efficacy, safety, and tolerability of PRO 140 monotherapy in maintaining viral suppression for over 24 months in patients who were stable on combination antiretroviral therapy on entry into the trials. Methods and Results Forty-one adult patients, infected exclusively with CCR5-tropic HIV-1 with viral loads <50 copies/mL, were switched from daily oral combination ART regimens to weekly PRO 140 monotherapy for 12 weeks. Participants who completed 12 weeks of treatment without experiencing virologic rebound were allowed to self-administer PRO 140 as a 350 mg subcutaneous injection weekly, for up to an additional 160 weeks. Participants were monitored bi-weekly for one year, and every four weeks thereafter for virologic rebound. PRO 140 provided virologic suppression in 23/41 (56.1%) participants for 12 weeks and was well tolerated. Ten (10) participants are currently ongoing, of which nine participants have completed more than two years of monotherapy treatment (47-129 weeks). Participants experiencing virologic rebound achieved full viral suppression upon re-initiation of oral combination ART regimen. Anti-PRO 140 antibodies were not detected in any patient, and no drug-related major adverse events or treatment discontinuations were reported. Conclusions PRO 140 has a potential to address an unmet need for a long-acting, single-agent, maintenance regimen for HIV infection in selected patients. Studies are underway to determine host and/or virologic factors that may predict treatment success on PRO 140 monotherapy. Moreover, it has sufficient potency for a prolonged period of monotherapy that it would be an excellent component of a multi long-acting drug combination.

PRO 140 Monoclonal Antibody to CCR5 Prevents Acute Xenogeneic Graft-versus-Host Disease in NOD-scid IL-2Rynull Mice.

Graft-versus-host disease (GVHD) is a prevalent and potentially lethal complication of hematopoietic stem cell transplantation. Humanized mouse models of xenogeneic GVHD are important tools used to study the human immune response in vivo. Here we used NOD-scid IL-2Rynull mice (NSG) transplanted with human bone marrow stem cells to evaluate the role of immune cell engraftment in the production of acute GVHD. PRO 140, a humanized monoclonal antibody targeting the chemokine receptor, CCR5, was used to evaluate its influence on bone marrow cell engraftment and modulation of acute GVHD. We evaluated the kinetics of engraftment by determining the percentage and absolute numbers of human CD45+ cells and CD3+ T cells from peripheral blood, spleen, and bone marrow in treated and control mice. With a dosing schedule of 2 mg of test or control antibody administered i.p. twice weekly, PRO 140-treated mice showed no signs of GVHD throughout the 70-day study period and gained weight until they were killed at 70 days for flow cytometry analysis. Control mice started losing weight after 25 days, showed classic signs of GVHD (ruffled fur, lethargy, severe hunching), and all were killed by day 54. The percentage and absolute numbers of human CD45+ cells in peripheral blood increased in both groups of mice throughout the 50-day comparison period and was lower in the PRO 140-treated mice at day 50. There was no difference in human CD45+ cells detected in bone marrow from control and PRO 140-treated killed mice. At this time point 76.1% and 68.2% of the hematopoietic cells from peripheral blood and from bone marrow, respectively, were of human lineage and 14.9% and 28%, respectively, were of mouse origin. With a schedule using 10-fold less dose of antibody (.2 mg i.p. twice weekly), PRO 140 still significantly modulated acute GVHD in terms of both weight loss and survival times, but no mice from either control or test group survived. By targeting the CCR5 chemokine receptor, PRO 140 modulated acute GVHD in a dose-response fashion in this xenogeneic mouse model without significantly altering engraftment.

Efeitos da quercetina na cicatrização de ferida cirúrgica contaminada em ratos Wistar / Efeitos da quercetina na cicatrização de ferida cirúrgica contaminada em ratos Wistar

A maioria das complicações na cicatrização é devida à inflamação. Comprovou-se que flavonóides interagem com ampla variedade de sistemas enzimáticos e bioquímicos, exercendo atividade antioxidante, antiinflamatória e antibacteriana. Não hárelatos sobre cicatrização cutânea em ratos com administração intraperitonial do flavonóide quercetina associado à incisão cirúrgica contaminada. Objetivo: Avaliar os efeitos da administração intraperitonial de quercetina no processo cicatricial da pele em ratos Wistar associados à incisão cirúrgicacontaminada com inóculo bacteriano padrão. Métodos: Utilizou-se 30 ratos: Grupo 1 (controle): procedimento cirúrgico contaminado, sem quercetina.Grupo 2: quercetina 24 horas antes do procedimento cirúrgico contaminado. Grupo 3: quercetina 24 horas antes e 24 e 48 horas após o procedimento cirúrgico contaminado. Grupo 4: quercetina 24 horas antes e 24, 48 e 72 horas após o procedimento cirúrgico contaminado. Grupo 5 (sham): procedimento cirúrgico sem contaminação e sem quercetina. Macroscopicamente, analisou-se deiscência de sutura, necrose de borda epiodermite, mensurando-se a área do abscesso. Microscopicamente analisou-se: reepitelização, intensidade do infiltrado inflamatório e avaliação dadistância entre as fibras musculares subcutâneas. Resultados: Os grupos com quercetina apresentarammenor área de abscesso (p<0,05) em relação ao controle. Deiscência e necrose não apresentaram diferençasignificativa (p>0,05) entre os grupos. Os grupos com quercetina apresentaram melhor reepitelização, celularidade compatível com fase mais avançada doprocesso cicatricial e menor quantidade de abscesso formado. Conclusões: A administração de quercetina intraperitonealmente mostrou-se eficaz sobre o processo cicatricial cutâneo em ratos Wistar associado à incisãocirúrgica contaminada com inóculo bacteriano padrão...

In most of the cases, complications in wound healing are due to inflammation. Flavonoids interact with a wide variety of biochemical and enzymatic systems, exerting antioxidant, antiinflamatory and antibacterial activity. There are no reports about cutaneous wound healing process in rats with intraperitoneal administration of quercetin associated with contaminated surgical incision.Objective: To evaluate the effects of theintraperitoneal administration of quercetin over cutaneous wound healing process in Wistar rats associated withcontaminated surgical procedure with a standard bacterial inoculum. Methods: Thirty rats: Group 1 (control): contaminated surgical procedure, without quercetin. Group 2: quercetin24 hours before the contaminated surgical procedure...

Antisense therapy for restenosis following percutaneous coronary intervention.

Recent advances in vascular gene transfer have shown potential new treatment modalities for cardiovascular disease, particularly in the treatment of vascular restenosis. The antisense approach to inhibiting gene expression involves introducing oligonucleotides complementary to mRNA into cells in order to block any one of the following processes: uncoiling of DNA, transcription of DNA, export of RNA, DNA splicing, RNA stability, or RNA translation involved in the synthesis of proteins in cellular proliferation. The approach includes the use of antisense oligonucleotides, antisense mRNA, autocatalytic ribozymes, and the insertion of a section of DNA to form a triple helix. Proof of principle has been established that inhibition of several cellular proto-oncogenes, including DNA binding protein c-myb, non-muscle myosin heavy chain, PCNA proliferating-cell nuclear antigen, platelet-derived growth factor, basic fibroblast growth factor and c-myc, inhibits smooth muscle cell proliferation in vitro and in several animal models. The first clinical study demonstrated the safety and feasibility of local delivery of antisense in the treatment and prevention of restenosis; another randomised clinical trial (AVAIL) with local delivery of c-myc morpholino compound in patients with coronary artery disease demonstrated its long-term effect on reducing neointimal formation, as well as its safety. These preliminary findings from the small cohort of patients require confirmation in a larger trial utilising more sophisticated drug-eluting technologies.