Vector supply isn’t the only challenge to the development and manufacturing of chimeric antigen receptor T-cell (CAR-T) therapies. The process of producing and delivering the therapies to patients can take 30 to 40 days, relying on cumbersome methods based on older cell expansion technologies repurposed for CAR-T.
In addition to expanding vector supply to meet growing demand, MilliporeSigma CEO Udit Batra, Ph.D., told GEN, his company is working to unclog two other bottlenecks to CAR-T development—by developing new technologies and a simpler production process that would create an end-to-end “closed box” system enabling the therapies to be produced entirely within the walls of the academic medical centers where patients are being treated
Dr. Batra discussed MilliporeSigma’s efforts to advance CAR-T therapy production, as well as its CRISPR business and some recent activity in biomanufacturing, in an interview conducted this week during the J.P. Morgan 36th Annual Healthcare Conference, held here at the Westin St. Francis Hotel.
“The full supply chain is extremely difficult, to say the least. And we have to work together to simplify it,” Dr. Batra told GEN.
The supply chain requires coordination between a patient’s primary oncology team and the manufacturing facility where the CAR-T therapy is produced. After patients are screened for eligibility and prepared for harvesting of their T cells via leukapheresis, the T cells are activated. A CAR gene is introduced into those T cells, creating CAR-T cells that are expanded in vitro for infusion in to the patient following “preconditioning” chemotherapy.
“One of the ways to simplify the process is to say, 'Why do I have to ship the T cells from the hospital to a central cell expansion center? Why can't I do the expansion at the hospital itself?' And we're working on that model.”
That model, he said, is expected to emerge through collaborations with undisclosed academic medical centers and technologists. MilliporeSigma—the name under which Merck KGaA operates its life science business in the U.S. and Canada—envisions carrying out manufacturing work now performed by the academic med centers, in facilities the company would establish for the purpose within those centers.
‘There’s a Clock Ticking’
“We are having some discussions on that front, talking to academic medical centers about building a cell therapy flow: Can we do the cell expansion on the hospital floor, as opposed to shipping the cells to another centralized facility? We would help them do the manufacturing, and then they would, of course, interface with the patient,” Dr. Batra said.
“The most important thing is, there's a clock ticking. Very often, these patients are in dire need of therapy. And time is passing, and each failed batch means that you have to restart.”
The development of the new technology and supply chain comes in addition to MilliporeSigma’s effort to address viral vector supply. Last year, the company completed an expansion of its Carlsbad, CA-based facility for manufacturing BioReliance® viral and gene therapy products. The value has not been disclosed for the expansion, through which the facility grew from 44,000 to 65,000 square feet, and now includes 16 modular viral bulk manufacturing cleanroom suites with single-use equipment and two fill/finish suites for gene therapy, viral vaccine and immunotherapy products.
The Carlsbad site, which MilliporeSigma inherited when it acquired Sigma-Aldrich in 2015, has also seen a multimillion-dollar investment in quality assurance at the site—spending that paid off when the facility passed inspections by both the FDA and European Medicines Agency.
In addition to producing more viral vectors, Dr. Batra said, MilliporeSigma has also worked to standardize their production through a template that entails separation and purification of the vectors.
“For customers who are brand new, and have never really developed a process, it can take as much as 18 months from start to finish,” Dr. Batra said. “It is a real bottleneck, and there are two solutions. One is, you put more capacity online, which is what we did. And second is to standardize the processing approach. And we're working on both.”
Doubling in Size
MilliporeSigma coalesces gene therapy and other novel modalities into a single business unit that Dr. Batra said has seen heavy investment from the company. While not quantifying that investment, he said the unit has doubled in size and grown to about 240 people based in viral vector manufacturing in Carlsbad, as well as employees in Glasgow, Scotland, where the company has another suite, and in St. Louis, MO.
In gene therapy, MilliporeSigma owns leading patents in classes covering genome cutting and replacement in mammalian cells through its own CRISPR/Cas9 technology. The technology is designed to enable researchers to replace a disease-associated mutation with a beneficial or functional sequence, a method important for creation of disease models and gene therapy.
The company’s CRISPR (clustered regularly interspaced short palindromic repeats) technology has been awarded patents in Europe, Australia, Canada, and Singapore. In the U.S., MilliporeSigma is awaiting a decision on its filing from the U.S. Patent and Trademark Office.
MilliporeSigma licenses composition of matter CRISPR/Cas9 patents from The Broad Institute, which is in a legal battle royal with Emmanuelle Charpentier, Ph.D., a director at the Max-Planck Institute in Berlin, the University of California (UC), and University of Vienna over who invented the gene-editing platform.
The company also holds exclusive rights from Sangamo to develop and market zinc finger DNA-binding protein (ZFP)-based laboratory research reagents marketed as CompoZr ® as well as ZFP-modified cell lines for commercial production of protein pharmaceuticals and ZFP-engineered transgenic animals. The rights cover research applications and cell line modifications, with Sangamo retaining rights for therapeutic applications.
MilliporeSigma has been involved in genome editing for about 15 years, having been the first company to offer custom biomolecules for genome editing globally (TargeTron™ RNA-guided group II introns and CompoZr zinc finger nucleases). MilliporeSigma was also first to manufacture arrayed CRISPR libraries covering the entire human genome.
Other topics covered by Dr. Batra are:
Biodevelopment Centers. MilliporeSigma has no plans to additionally expand its network of BioReliance® End-to-End Biodevelopment Centers, through which MilliporeSigma aims to work with small-scale drug manufacturers working on early-phase clinical trials by offering process development capabilities and services.
Over the past year, the company opened centers in Burlington, MA, and Shanghai, citing the success of its biodevelopment center in Martillac, France, a fully operational single-use, GMP facility for manufacturing clinical-stage batches. ”Geographically, one in Europe, one in Asia, and one in the U.S. is fine for now,” Dr. Batra said. “I don’t think there's reason to think at this stage that we will expand any further immediately.”
Chromatography. MIlliporeSigma is “starting to build our presence” in chromatography following a pair of moves late last year. The company expanded its single-use chromatography portfolio by acquiring Natrix Separations for an undisclosed sum, and a month later launched Eshmuno® P anti-A and Eshmuno® P anti-B affinity chromatography resins, designed to remove anti-A and anti-B isoagglutinin antibodies during the manufacturing of plasma-derived immunoglobulin (Ig) therapies.
“When we look at different steps in the process in bioproduction, chromatography was one where we were not present a few years ago, so we decided to launch our own internal programs, and those were highly successful,” Dr. Batra said, acknowledging that the company remains second to GE Healthcare. “The acquisition of Natrix just augments what we were doing already.”