ABSTRACT
Strategies for targeting CD47 are becoming a hot spot of cancer immunotherapy. However the ubiquitous expression of CD47, especially on the RBC, makes the targeted therapy facing safety risk issues. So, how to balance the safety and efficacy during CD47 inhibition is currently a major question. We had reported an anti-CD47 antibody ZF1 with potent anti-tumor effect. In this study, we further developed and assessed a novel fully human anti-CD47 antibody, AMMS4-G4, derived from ZF1 using affinity maturation. AMMS4-G4 exhibited equivalent anticancer effects with Hu5F9-G4, a humanized anti-CD47 antibody in clinical trial, on the potential of inducing significant phagocytosis of tumor cells in vitro and prolonging the survival of leukemia xenografted mice. Additionally, AMMS4-G4 significantly inhibited the growth of grafted solid tumors by enhancing macrophage infiltration and modestly enhanced the anti-tumor activity of opsonizing antibody and antiangiogenic therapy. In cynomolgus monkeys, AMMS4-G4 was safely administered, was well tolerated at doses of 30 and 60â¯mg/kg, and did not produce serious adverse events, except for the reversible anemia, which was observed after 3 days and started to recover from 9 days later. Remarkably, it was proved by in vitro assay that Hu5F9-G4 induced RBC hemagglutination which wasn't observed in AMMS4-G4. On the whole, AMMS4-G4 was demonstrated to be a promising candidate with great potential and safe profile for cancer immunotherapy.
Subject(s)
Antibodies, Monoclonal/therapeutic use , CD47 Antigen/immunology , Immunotherapy/methods , Neoplasms/therapy , Animals , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/immunology , Dose-Response Relationship, Immunologic , Humans , Immunotherapy/adverse effects , Macaca fascicularis , Mice, Inbred BALB C , Mice, Nude , Phagocytosis , Xenograft Model Antitumor AssaysABSTRACT
<p><b>OBJECTIVE</b>To evaluate the use of Delorme procedure for full-thickness rectal prolapse.</p><p><b>METHODS</b>A series of 25 patients with full-thickness rectal prolapse were treated by Delorme procedure in four institutions between March 2005 and June 2010. The clinicopathological data were analyzed retrospectively.</p><p><b>RESULTS</b>There were 9 males and 16 females. The mean age was 52(46-72) years old. All the procedures were successfully performed. There were no perioperative deaths. The mean operative time was 65(45-150) min. The intraoperative bleeding was 58(20-200) ml. The mean length of hospital stay was 8.5(5-14) days. Anastomosis dehiscence occurred in 1 patient at post-operative day 7 who was managed under anesthesia. Minor complications occurred in 8(32%) patients, including urinary retention(n=3), intractable pain(n=1), and bowel obstruction(n=4). The follow up time ranged from 2 to 6 years with a median of 3.5 years. Prolapse recurrence was observed in 1(4%) patient during the follow up. The remission rates of fecal incontinence, constipation, bleeding were 37.5%(6/16), 45.5%(5/11), and 15.4%(2/11), respectively. The Wexner incontinence score significantly decreased (median, 5.0 vs. 9.0, P<0.01). The resting pressure and maximum squeeze pressure increased significantly after surgery, while the initial volume and maximal tolerance volume decreased significantly(All P<0.01).</p><p><b>CONCLUSIONS</b>Delorme procedure is safe and easy to perform. The anorectal function is improved after surgery. Therefore it should be considered the procedure of choice for rectal prolapsed.</p>
