Anti-CD3 Drug Keeps Diabetes at Bay No Drug Has Ever Delayed Islet Cell Destruction

news IN this section β-thalassemia Gilead, Galapagos Biotech news from gene therapy in $5.1 billion tie around the world approved p1102 p1104 p1106 Anti-CD3 drug keeps diabetes at bay No drug has ever delayed islet cell destruction. Now that teplizumab has, the challenge turns to identifying eligible recipients for the treatment. he first drug to ever slow the progression from pre-diabetes to Tclinical type 1 diabetes is one step closer to reaching the market. On August 5, the US Food and Drug Administration (FDA) granted breakthrough therapy designation to teplizumab, a CD3-targeted antibody from Provention Bio, to prevent or delay type 1 diabetes onset among children and adults at high risk of developing the disease. The regulatory distinction comes after a June report showing that teplizumab postponed the onset of symptomatic disease by a median of two years compared with placebo in patients who took the drug for 14 days (N. Engl. J. Med. 381, 608–613, 2019). “It’s a very prolonged effect after a single two-week course of the antibody,” says Lucienne Chatenoud, an immunologist from the Necker Hospital for Sick Children in Paris who was not involved in the study. “This is, in view of all clinical diabetologists, a real measure Should a treatment to push back the age of type 1 diabetes onset become available, screening programs of robustness... You are really delaying the to identify children at a markedly elevated risk will be critical. One such European effort is the Global onset of insulin therapy.” Platform for the Prevention of Autoimmune Diabetes, which has undertaken to screen 100,000 Although some researchers maintain newborns for disease-associated variants, including polymorphisms in human leukocyte antigens (HLA) that larger confirmatory trials are still of the DR and DQ isotypes. Credit: KKStock / Alamy Stock Photo needed to prove the benefit of teplizumab, especially in younger children, Provention Bio’s chief executive Ashleigh Palmer says the company now intends to use the dependent on daily insulin injections. study. “I can assure you, if you talk to results of the 76-person study to support a Numerous approaches have attempted to people who have diabetes, they would jump marketing application for people who have prevent or stop islet cell destruction, but so up and down” for two years free of their autoantibodies against pancreatic islets or far, all have failed. Teplizumab now ushers disease. But, she notes, identifying would-be against insulin and are thus fated to develop in the possibility of offering a drug to people drug recipients in that preventative setting type 1 diabetes. Provention also has an who test positive for markers of beta cell remains a challenge. ongoing phase 3 trial evaluating the same autoimmunity but who do not yet have Teplizumab traces its roots back more drug in children and adolescents with newly symptoms of disease. 30 years to the laboratory of Jeffrey diagnosed disease. “I seriously can’t express enough Bluestone, an immunologist now at the Type 1 diabetes is one of the most what a landmark trial this is,” says Carla University of California, San Francisco. In common chronic diseases of childhood. It is Greenbaum, an endocrinologist at the the late 1980s, Bluestone began working prompted by the autoimmune destruction Benaroya Research Institute in Seattle, with Ortho Pharmaceutical to modify the of insulin-producing beta cells in pancreatic Washington, who leads TrialNet, the company’s OKT3, an agonistic CD3-directed islets and leaves affected individuals academic consortium behind the prevention murine monoclonal antibody that the FDA NATURE BIOTECHNOLOGY | VOL 37 | OCTOBER 2019 | 1099–1109 | www.nature.com/naturebiotechnology 1099 news had approved a year earlier for reducing symptoms of EBV-related disease, but Lung Biotechnology tags acute rejection of transplanted organs. He neither did they do better than a placebo iBio for bioink production first mutated the Fc region of OKT3 to at preserving levels of C-peptide or other Lung Biotechnology continues making decrease binding of target receptors, thereby markers of diabetes control. After running inroads toward its goal of manufacturing minimizing crosslinking of the T-cell one last dose-finding follow-up study in 30 3D bioprinted lungs, with a newly receptor/CD3 complex that can trigger individuals, GlaxoSmithKline eventually announced partnership with iBio to scale cytokine release. He then humanized the halted further development last year. up bioink production. The partnership molecule to reduce its immunogenicity In the case of teplizumab, investigators ran follows a 2018 deal with the Israeli (Transplantation 57, 1537–1543, 1994) and a study that Eleanor Ramos, Provention’s chief regenerative medicine company CollPlant teplizumab was born. medical officer and chief operating officer, to license and develop technology for After initial testing in kidney transplant describes as “inherently flawed.” For starters, creating organ scaffolds from bioink recipients, Bluestone teamed up with the phase 3 Protégé trial enrolled a diverse derived from recombinant human Kevan Herold, a clinical immunologist global population, including patients from collagen. Lung Biotechnology, a public now at the Yale School of Medicine in New India who tended to have more advanced benefit corporation subsidiary of United Haven, Connecticut, to start evaluating disease than those from North America, Therapeutics, will use the scaffolds to teplizumab in patients with recent-onset Europe and Israel—and that heterogeneity create bioprintable lungs. iBio will use type 1 diabetes in 1999. Within a year, a “seemed to dilute any effect” of the drug, its FastPharma platform—an automated European group led by Chatenoud and Herold says. The study also had no minimum plant-based protein expression system Bart Keymeulen of the Free University C-peptide requirement: patients only had to combined with hydroponics and glycan of Brussels–VUB began its own study have detectable levels, an indicator of beta engineering—to scale up production of otelixizumab, another humanized cell function but not necessarily a plentiful of CollPlant’s bioink for fabricating Fc-mutated immunoglobulin G1 antibody reserve of insulin-producing cells. that, like teplizumab, targets the ε chain of lung scaffolds that can then be taken to “I can assure you, if you talk clinical trials. Additional collaborations the CD3 receptor. (The antibodies differ might be needed to optimize and expand primarily in how they limit Fc receptor to people who have diabetes, binding, with otelixizumab mutated the process for producing commercial they would jump up and down” quantities, iBio said. specifically to avoid glycosylation.) Recombinant human collagen bioink With either anti-CD3 agent, a short is being used with various bioprinting course of treatment started within a few But perhaps the biggest problem with technologies. CollPlant’s bioink— months of diagnosis helped preserve the trial was its primary outcome measure. extracted from the leaves of tobacco plants C-peptide levels, a byproduct of insulin MacroGenics came up with a composite genetically engineered with five human production that serves as an indirect measure defined by insulin usage and genes to produce collagen—includes light- measure of remaining beta cell function. glycemic control as defined by hemoglobin sensitive compounds that can modify the The benefits also lasted for years and the A1c (HbA1c). It ultimately doomed the study. bioink to match natural tissue properties, therapies proved generally tolerable. At One year after treatment, using these criteria, ranging from cartilage to adipose tissue. worst, teplizumab caused cytokine release a similar percentage of patients in the placebo Other groups, like the biotech syndrome–like toxicity in a minority of and teplizumab arms of the Protégé study met company Organovo, are using 3D recipients, owing to the modest T-cell the primary endpoint of low insulin usage bioprinting to generate a spectrum activation, and many otelixizumab recipients and HbA1C levels in a healthy range. of tissues, including liver, kidney and experienced transient symptoms of Epstein– C-peptide levels, however, were better intestine, mainly for lab-on-a-chip Barr virus (EBV) mononucleosis owing to preserved in teplizumab-treated patients, technologies. Bioprinting complex organs viral reactivation among patients with latent both one and two years out from treatment. has remained out of reach, and few prior infections. And there were subgroups—younger companies have attempted to produce In the mid-2000s, MacroGenics patients, those who were recently diagnosed lungs. But 3D bioprinted lungs took a step secured the rights to teplizumab and at the time of trial enrollment, participants forward in May, with the publication of Tolerx in-licensed otelixizumab. Both from the United States—that experienced findings in Science from a Rice University biotech companies then turned around and especially pronounced benefits. team demonstrating a stereolithographic inked co-development deals with larger After Provention acquired the asset from method of using photoactivated liquid pharmaceutical partners—MacroGenics with MacroGenics in May 2018, the company resins to create hydrogels with vascular Eli Lilly, Tolerx with GlaxoSmithKline— took the lessons of those post hoc analyses architectures that mimic lung air sacks. and launched phase 3 trials in new-onset to heart and designed a 300-person study The researchers

Load more