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December 06, 2016

Back to School for Biotech

How Academia and Industry Can Collaborate to Advance Biologic Drug Development and Manufacturing

Back to School for Biotech

  • The unprecedented pace of discovery in biological sciences is opening potentially transformative new modalities to treat many human diseases. Cell therapy, gene therapy, immunotherapy, epigenetic approaches to regulate gene expression, and other novel therapeutic strategies offer both an abundance of opportunity and significant challenges for companies trying to commercialize new biologics.

    To grapple with the demands of the science and the technology needed to translate discoveries into approved biologic therapies, some start-up biotechs and established biopharmaceutical companies are building new bridges with academia. On the campus side of the equation, core facilities reap service revenue and academic investigators gain early-stage funding to explore ideas that are not ready for NIH or venture capital support. Several examples of these novel relationships were presented at a panel discussion at the Biotech Week in Boston Conference (formerly called BioProcess International East).

    “Academic and industry collaboration for translational biologics research and development is an underutilized model,” said Kamal Rashid, Ph.D., research professor and director of the Biomanufacturing Education and Training Center at Worcester Polytechnic Institute (WPI), who organized and moderated the discussion. “We want to shed light on how some of these relationships are working today, so we can expand the model for the benefit of companies, academic researchers and, ultimately, the patients who will benefit from these powerful new therapies.”

    Panelists presented examples of ongoing collaborations for early research, proof-of-concept studies, process scale-up, manufacturing for clinical studies, workforce development, and best practice analysis for companies making approved biologics.

    Collaborations for emerging cell therapies were discussed by Jerome Ritz, M.D., executive director of the Connell O’Reilly Cell Manipulation Core Facility at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School.  “Working on cell therapies remains a very difficult, labor-intensive process,” Dr. Ritz said. “In my view, no one can do all of this on their own. You need to collaborate.”

    A key mission of the cell manipulation core facility is to support the stem cell transplantation programs at Dana-Farber/Brigham and Women’s Hospital, and Boston Children’s Hospital. These programs have grown significantly over the past 10 years and the lab now provides stem cell products for over 600 patients per year, Dr. Ritz explained. The facility also provides complex GMP cell manufacturing support for clinical trials at all of the Harvard-affiliated hospitals and other academic health centers in Massachusetts. These studies, which represent collaborative efforts between clinical investigators and laboratory scientists at multiple institutions and private companies, involve genetically modified stem cells, cancer vaccines, chimeric antigen receptor (CAR) T cells, regulatory T cells, mesenchymal stromal cells (MSCs), and extensively modified hematopoietic stem cell products.

    In recent years, Dr. Ritz’s team has manufactured cells to support 30 to 40 clinical trials and 10 to 15 Investigational New Drug (IND) filings. The core facility staff has grown to 50 people and further expansion is planned to meet increasing demand. “We start at the early stage, working with the investigators, either in academia or industry,” Dr. Ritz said. “Our role is to help them develop new therapies, and to test the safety and efficacy of these new approaches in early phase clinical trials. Once successful cell therapies are identified, manufacturing procedures would be transferred to larger scale industrial facilities.”

    A perceived barrier for academic/industry collaborations has been the incompatibility of intellectual property policies, “but IP can be managed and should not be a stumbling block anymore,” said Mark  Klempner, M.D., executive vice chancellor, MassBiologics and professor of medicine at the University of Massachusetts Medical School (UMMS). “At MassBiologics we work very well with our industry partners, and I believe at most universities today you will find that IP is handled effectively.”

    MassBiologics, a division of UMMS since 1997, was established in 1894 by the state’s Board of Health to make diphtheria antitoxin. MassBiologics has a long history of developing and manufacturing vaccines, immunoglobulins, and other biologics in support of public health. It is the only nonprofit, publicly owned, FDA-licensed vaccine and biologics manufacturer in the United States. “We are not your typical academic facility,” Dr. Klempner said.

    Over the past 10 years, MassBiologics has expanded its vaccine and monoclonal antibody cGMP manufacturing facilities and also broadened its discovery research and process development capabilities on its campus in the Mattapan section of Boston. In 2015 it opened a Vector Manufacturing Center in Fall River, MA, to support gene therapy programs. “In addition to the discovery work we continue to do, we have developed this collaborative infrastructure that’s available for contract process development, contract manufacturing, aseptic fill and finish,” Dr. Klempner explained. “We also will collaborate with smaller companies to provide access to the technologies they need but can’t always afford, along with the process development expertise of our team.”

    Panelist David Dismuke, Ph.D., director of vector production at the start-up gene therapy company Voyager Therapeutics, explained how his company’s strategic alliance with MassBiologics is accelerating their development processes. Voyager’s proprietary technology uses adeno-associated virus (AAV) vectors to deliver constructs that either express healthy levels of specific proteins or knock down expression of disease-causing genes. “We are targeting diseases of the central nervous system, often through direct administration. So, manufacturing a safe and effective product is paramount,” Dr. Dismuke noted.

    In-house expertise at Voyager focuses on optimizing its AAV platform and the sequences of DNA embedded for delivery within the AAV capsids. Success at the bench scale, however, does not automatically scale up to levels needed to make clinical quantities. “Our objective has been to transfer our early development baculovirus/Sf9 insect processes at 250 liters, switch from a paddle bioreactor to a stir-tank, and increase our vector recovery, which are not trivial matters,” Dr. Dismuke said. “Our collaboration with MassBiologics has been critical. We have been able to utilize their experience in process scale-up and regulatory compliance to achieve our goal of developing a commercially viable process, and we have been able to do so in a collaborative and efficient manner.”

    From a larger company perspective, Sridaran Natesan, Ph.D., vp of strategic initiatives and scientific relations, North America, at Sanofi, presented his company’s emerging model for academic collaborations. “Sanofi used to be a small- molecule company. Now, 70% of our programs are in biologics,” Dr. Natesan said. “So the early-stage pipeline is the challenge. There are so many emerging modalities to consider, and we don’t have the internal expertise to evaluate or develop them all. So where do we invest?”

    An important part of the answer to that question for Sanofi is to build closer collaborations with academic investigators. The company first piloted the concept at MIT and has since broadened the program to seven universities and hospitals in the United States. Sanofi invites research teams to submit proposals and the company funds about 25 each year.  “We are looking for early stage programs that are not ready for NIH funding or venture funding, but that we are excited about,” Dr. Natesan explained.

    Among the best practices Sanofi now applies to the program: academic investigators must identify a clear path to the clinic; a program manager from Sanofi is dedicated to work on the academic partnerships full-time and remain in regular, direct contact with the investigators; all involved must be willing to make course corrections as the program evolves. “Communication is really the key,” Dr. Natesan concluded.

    Panelist Susan Roberts, Ph.D., professor and head of chemical engineering at WPI, gave an overview of 15 collaborations her department now has with various life sciences companies, including equipment manufacturers seeking external feedback on their latest designs. Many of those collaborations take the form of WPI’s Major Qualifying Project (MQP) which is a year-long undergraduate research project students complete in their senior year.

    “Every undergraduate at WPI has to complete an MQP, and they are very rigorous projects done under the direct supervision of faculty,” Dr. Roberts said. “Many MQPs are industry-sponsored projects. So if you have an idea you want to test, or a problem you need to solve, then the MQP program at WPI is a great way to start.”

    Academic-industry collaborations also extend beyond early research and help companies already making approved biologics, with benchmarking, best-practice sharing and technology assessment and development., For example, contamination in an FDA-approved process is, perhaps, the greatest operational risk biomanufacturers face. It’s a sensitive subject that companies prefer not to discuss publicly. MIT saw an opportunity to help the industry share important information and founded the Consortium on Adventitious Agent Contamination in Biomanufacturing (CAACB).

    “We act as a neutral hub,” said Stacy Springs, Ph.D., who leads the CAACB and directs the Biomanufacturing Research Program (BioMAN) at MIT. “We work with the industry to collect data from member companies, anonymize it, analyze it, and share it back with industry so companies can learn from industry experience, and better prepare for similar risks.”

    Focusing on that window of “precompetitive collaboration”, MIT is also developing a similar program for advanced analytical and process control strategies. “We are asking, ‘How can we be faster, smaller, and integrated with our analytics for both protein products and emerging products like cell and gene therapies?’ ” Dr. Springs asked.

    MIT is also working with a consortium of universities and companies around the country (including the University of Delaware, WPI, UMass, and others) seeking funding from the U.S. Commerce Department's National Institute of Standards and Technology (NIST) to establish a Manufacturing Innovation Institute as part of the ManufacturingUSA National Network of Manufacturing Innovation, she said.

    In addition to translational research studies at WPI, the university offers hands-on programs at the Biomanufacturing Education and Training Center (BETC), a center built-out like a commercial facility, from cell banking through pilot-scale process, downstream capture, and purification. “Training is not a luxury for companies, it’s an FDA requirement,” Dr. Rashid noted. “The benefit of our center is that people can learn hands-on, and if they goof up, it’s not a million dollar mistake.” Over the past three years, more than 30 companies have sent employees to a range of intensive upstream and downstream training programs at the BETC, he said. 

    Summing things up at the end of the panel discussion, Dr. Rashid said. “I think what we learned here is that collaborations between academia and industry can be very successful, and I hope that others will benefit from the excellent examples presented here today.”

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