Frontier of therapeutic antibody discovery:The challenges and how to face them

Therapeutic monoclonal antibodies have become an important class of modern medicines.The established technologies for therapeutic antibody discovery such as humanization of mouse antibodies,phage display of human antibody libraries and transgenic animals harboring human IgG genes have been practiced successfully so far,and many incremental improvements are being made constantly.These methodologies are responsible for currently marketed therapeutic antibodies and for the biopharma industry pipeline which are concentrated on only a few dozen targets.A key challenge for wider application of biotherapeutic approaches is the paucity of truly validated targets for biotherapeutic intervention.The efforts to expand the target space include taking the pathway approach to study the disease correlation.Since many new targets are multi-spanning and multimeric membrane proteins there is a need to develop more effective methods to generate antibodies against these difficult targets.The pharmaceutical properties of therapeutic antibodies are an active area for study concentrating on biophysical characteristics such as thermal stability and aggregation propensity.The immunogenicity of biotherapeutics in humans is a very complex issue and there are no truly predictive animal models to rely on.The in silico and T-cell response approaches identify the potential for immunogenicity;however,one needs contingency plans for emergence of antiproduct antibody response for clinical trials.

Fabricating 3-dimensional human brown adipose microtissues for transplantation studies

Transplanting cell cultured brown adipocytes(BAs)represents a promising approach to prevent and treat obesity(OB)and its associated metabolic disorders,including type 2 diabetes mellitus(T2DM).However,transplanted BAs have a very low survival rate in vivo.The enzymatic dissociation during the harvest of fully differentiated BAs also loses significant cells.There is a critical need for novel methods that can avoid cell death during cell preparation,transplantation,and in vivo.Here,we reported that preparing BAs as injectable microtissues could overcome the problem.We found that 3D culture promoted BA differentiation and UCP-1 expression,and the optimal initial cell aggregate size was 100μm.The microtissues could be produced at large scales via 3D suspension assisted with a PEG hydrogel and could be cryopreserved.Fabricated microtissues could survive in vivo for long term.They alleviated body weight and fat gain and improved glucose tolerance and insulin sensitivity in high-fat diet(HFD)-induced OB and T2DM mice.Transplanted microtissues impacted multiple organs,secreted protein factors,and influenced the secretion of endogenous adipokines.To our best knowledge,this is the first report on fabricating human BA microtissues and showing their safety and efficacy in T2DM mice.The proposal of transplanting fabricated BA microtissues,the microtissue fabrication method,and the demonstration of efficacy in T2DM mice are all new.Our results show that engineered 3D human BA microtissues have considerable advantages in product scalability,storage,purity,safety,dosage,survival,and efficacy.

Secukinumab provided significant and sustained improvement in the signs and symptoms of ankylosing spondylitis:results from the 52-week,PhaseⅢChina-centric study,MEASURE 5

Background:Secukinumab demonstrated sustained efficacy in patients with ankylosing spondylitis(AS)through 5 years in pivotal Phase III studies.Here,we present efficacy and safety results(52-week)of secukinumab in patients with AS from the MEASURE 5 study.Methods:MEASURE 5 was a 52-week,Phase III,China-centric study.Eligible patients were randomly assigned(2:1)to receive subcutaneous secukinumab 150 mg or placebo weekly for the first five doses and then once every 4 weeks(q4w).All placebo patients switched to secukinumab 150 mg q4w starting at Week 16.Primary endpoint was Assessments of SpondyloArthritis international Society(ASAS)20 at Week 16.Randomization was stratified by region(China vs.non-China).Results:Of 458 patients(secukinumab 150 mg,N=305;placebo,N=153)randomized,327(71.4%)were from China and 131(28.6%)were not from China.Of these,97.7%and 97.4%patients completed Week 16 and 91.1%and 95.3%(placebo-secukinumab)patients completed Week 52 of treatment.The primary endpoint was met;secukinumab significantly improved ASAS20 response at Week 16 vs.placebo(58.4%vs.36.6%;P<0.0001);corresponding rate in the Chinese population was 56.0%vs.38.5%(P<0.01).All secondary efficacy endpoints significantly improved with secukinumab 150 mg in the overall population at Week 16;responses were maintained with a trend toward increased efficacy from Week 16 to 52.No new or unexpected safety signals were reported up to Week 52.Conclusions:Secukinumab 150 mg demonstrated rapid and significant improvement in signs and symptoms of AS.Secukinumab was well tolerated and the safety profile was consistent with previous reports.Efficacy and safety results were comparable between the overall and Chinese populations.