May Spotlight

Welcome New BPI Colleague

In April, BioProcess International waved a reluctant goodbye to European strategic marketing consultant Joanna Hendrikx. Pregnant with her second child, she is looking forward to devoting herself exclusively to motherhood. We will miss her energy, finesse, and sense of humor even as we welcome our new colleague taking over her role here.

Victoria Biscoe has a long history with Informa, our parent company, having joined in 2010 as a key account manager for the Informa Life Sciences conference division in Europe. In 2012, she moved to the Pharmaceutical Training Institute division as a customized training consultant. That led to her role as head of customized training for Knect365 Learning in 2015 — and ultimately to BPI.

Before Informa, Victoria was a recruitment consultant for Acme Appointments in London. She has a bachelor of science degree in psychology from Loughborough University, where she also played netball on a national college-sports champion team. BPI is excited to welcome her aboard!

Aggregation and ADCs

Experts at specialist contract services company ADC Biotechnology (ADC Bio) warn that some best-in-class antibody–drug conjugates (ADCs) are overlooked because of critical aggregation-control problems. Contract development and manufacturing organizations (CDMOs) have trouble with such products for clinical testing and economical manufacturing. There is an urgent need for techniques that prevent formation of soluble high–molecular-weight (HMG) aggregates of ADCs that can cause severe adverse immune responses in patients. This warning comes as full-service CDMOs increasingly invest in conjugation and ADC facilities.

This represents “a major challenge in the ADC pipeline,” says ADC Bio’s CEO Charlie Johnson. “You may have a candidate that looks promising but in practice can’t be commercialized — unless aggregation control systems are put in place. We are seeing a great deal of excitement from pharma companies seeking to invest in ADC therapeutics. But applying conventional manufacturing techniques will see the drugs fail or endure very long periods in development. From the vendor side, there is considerable investment across the industry in facilities, but that alone will not give you the capabilities to commercialize optimal ADC therapeutics. And that is ultimately a failure to patients desperately in need of new life-saving therapies.”

He says that is especially the case with ADCs that incorporate pyrrolobenzodiazepine dimers (PBDs) or duocarmycin payloads. Such drugs are difficult to develop primarily because the payloads are very hydrophobic. Despite making up only 2% of a combined ADC molecule, such payloads can dramatically increase the drug substance’s propensity to aggregate. So effective aggregation-control solutions are critical.

One method of aggregation control is by physically segregating antibodies from each other during conjugation. For example, ADC Bio’s proprietary “Lock-Release” technology platform immobilizes antibodies onto a solid-phase support to segregate them and prevent aggregation during conjugation. Afterward, the ADCs are subsequently released into formulation with stabilizing excipients that suppress aggregation.

“Effective aggregation control technologies can be the difference between whether an ADC makes it to market as a commercially viable product or fails,” Johnson says. “We’re coming to the ADC market from a completely different direction: We are not an all-purpose CDMO. We realized that there was a problem and consequently developed a proprietary technology.”

Oral Peptide Active Agents Advance

Peptides represent a potential billion-dollar market in the pharmaceutical industry. Worldwide, some 500 peptide-based medications are currently in clinical trials. Until recently, all such medications have had to be injected. But a research team led by the Technical University of Munich (TUM) appears to have solved the problem of making them orally available (1).

“Peptides are wonderfully well suited as medication,” says Horst Kessler, professor at the Institute for Advanced Study at TU Munich. “The body already uses them as signaling molecules, and when they have done their job, they can be recycled — no accumulation, no complicated detoxification.”

Examples of these short chains of amino acids include insulin (51 amino acids) controlling the metabolism of sugar and cyclosporine (11 amino acids) that suppresses organ rejection after transplants. Because proteins make up a major part of our diet, human stomach and intestines harbor countless enzymes that break peptide bonds. No medication based on unmodified peptides would survive passage through the gastrointestinal tract. Even when modified peptide compounds make it through the stomach intact, they face intestinal wall cells that prevent their absorption into the bloodstream. Thus, active peptide agents generally have been administered by injection.

Using a ring-shaped model peptide made of the simplest amino acid (alanine), scientists tried replacing different hydrogen atoms in the peptide bonds with methyl groups. Cellular tests by collaboration partners in Israel showed that those specific peptide variants are absorbed quickly.

The team chose integrin receptors (which convey information about a cell’s environment to its interior) as a target. A sequence of the three amino acids — arginine, glycine, and aspartic acid — is necessary for docking at those receptors. Kessler’s coworkers incorporated the key sequence at different positions in their model peptide to create new variants. However, both the negatively charged side chain of aspartic acid and the positively charged arginine turned out to be problematic. The team managed to mask the charged groups of both amino acids with protecting groups. However, that deprived peptides of their ability to bind to the target molecules. The problem was overcome by selecting the right protective groups. Those molecular groups are split off again by enzymes that are ubiquitous in human blood. Thus, the peptide’s pharmaceutical effect is restored when it arrives at its destination.

Cell-based testing has shown that the new hexapeptides have a biological effect, stimulating blood-vessel growth in low doses. When mice have been fed the masked hexapeptide, the effects are the same as in those that were injected with the unmasked version.

“In the past,” says Kessler, “experts have designated the oral availability of peptide-based medications as the ‘holy grail of peptide chemistry.’ Our work provides a strategy for solving the challenges of stability, absorption in the body, and biological effectiveness. In the future, this will greatly simplify the creation of peptide medication that can be given easily in fluid or tablet form.”

Reference 1 Weinmüller M, et al. Overcoming the Lack of Oral Availability of Cyclic Hexapeptides: Design of a Selective and Orally Available Ligand for the Integrin Alphavbeta3. Angewandte Chemie Int. Ed. 56, 2017: 16405–16409; doi:10.1002/anie.201709709. https://doi.org/10.1002/anie.201709709.

New Stem Cell Product Launches in February

In February 2018, orthobiologics company Royal Biologics announced the launch of its Amnio-Maxx stem-cell product derived from human amniotic placental tissue. The company specializes in research and advancement of regenerative cellular therapy.

Amnion is placental tissue that surrounds and protects a fetus during in utero development. The tissue consists primarily of fibrillar and membranous collagens, elastin, and a mix of cytokines and growth factors that are unique to placental tissues. Those benefit a growing fetus and also have been proven effective for treating and protecting wounds as well as creating an environment favorable to regeneration of healthy tissue in patients.

“Studies in published literature support the successful and safe clinical use of repurposing this versatile tissue to improve outcomes in wound management,” says Royal Biologics CEO Salvatore Leo. “This tissue, including amniotic fluid, can be used safely in a variety of surgical and clinical settings and can develop into various tissue types, including skin, cartilage, cardiac tissue, nerves, muscle, and bone.”

Amnion has been used in a number of clinical settings for applications such as spinal, neurologic, and bariatric surgeries; sports medicine; wound care; and trauma. Placental tissue comes in two forms: liquid amnion and dehydrated dual-layer patches. The Amnio-Maxx product serves as a safe, natural covering that improves normal wound healing; reduces inflammation, fibrosis, and scarring at surgical sites; and decreases pain.

To ensure safety and maximize performance of each graft, Amnio-Maxx products are sterilized using a proprietary process. Aseptic donor-tissue collection is performed by licensed tissue establishments. All placentas used come from planned Cesarean section procedures, which helps to minimize potential contamination during recovery. In addition, placental donors go through rigorous prescreening qualification and are tested to confirm that they are free from disease.

Partners to Further Regenerative Medicine

Joining with more than 100 organizations seeking to further the field of tissue engineering and regenerative medicine, The American Society of Mechanical Engineers (ASME) has partnered with the Advanced Regenerative Manufacturing Institute (ARMI). Founded in 1880 as the American Society of Mechanical Engineers, ASME is a not-for-profit professional organization enabling collaboration, knowledge sharing, and skill development across all engineering disciplines, while promoting the vital role of engineers. In 2017, ASME launched the Alliance for Advanced Biomedical Engineering (AABmE), which provides technical articles, reports, and other resources on a variety of topics such as cell therapy, thermal medicine, medical devices, and 3D printing.

The ARMI partnership unites ASME with a consortium of organizations from industry, government, academia, and the nonprofit sector working to develop next-generation manufacturing processes and technologies for cells, tissues, and organs. Based in Manchester, NH, ARMI will receive nearly US$300 million in public–private investment from those groups to develop scalable manufacturing processes for engineered tissues and organs. Those efforts are supported by 47 industrial partners, 26 academic and academically affiliated partners, and 14 government and nonprofit partners.

“The intent of this alliance is to grow as a comprehensive resource for the biomedical engineering community,” says Christine Reilley, business development director of Healthcare at ASME. “Given our increasing focus in biomedical engineering, we believe that the society can contribute to the goals of ARMI as the coalition works to revitalize American manufacturing and incentivize companies to invest in new technology development.”

Pall Names New Biotech Business Unit

Pall Corporation created a new business unit in January within its Life Sciences division: Pall Biotech (www.pall.com/biotech) named to reflect more clearly its market focus on the crossover between biopharmaceutical and other biotechnology advances. The change does not affect current or prospective company operations.

“As the lines between the biopharmaceutical and biotechnology sectors continue to merge,” said Mario Philips, vice president and general manager of Pall Biotech, “our commitment is stronger than ever to develop and deliver end-to-end capabilities with cutting-edge technologies and services. The name Pall Biotech reflects a more focused approach to serving these high-growth market segments. It also reflects our dedication to reducing costs while increasing efficiency and quality for today’s developer of sensitive biologic products, including monoclonal antibodies (MAbs), recombinant proteins, viral vaccines, and cell and gene therapies.”

The company expects both its industry partnerships and alignment with regulatory agencies to improve the integrated and stand-alone elements of its total bioprocessing solutions portfolio. That consists of standard configurable single-use, reusable (stainless steel), and hybrid technologies for fed-batch and continuous processes across upstream, downstream, and formulation–filling applications. The goal is to help customers accelerate time to market with cost-effective, robust, and reliable integrated solutions.

“Pall Biotech does not make drugs; we enable drug manufacturers to have rapid transition from preclinical to commercial manufacturing,” explained Martin Smith, Pall’s chief technology officer. “In 2018, our life sciences division boasts the most complete solutions from drug discovery through delivery, with Pall Laboratory for research and discovery, Pall Biotech enabling next-generation manufacturing processes, and Pall Medical for patient delivery.”

Moving forward in 2018, the Pall Biotech team is focused on developing and launching integrated, end-to-end bioprocessing technologies and services that can improve how medicines are made around the globe. For example, the Cadence inline diafiltration (ILDF) was recognized as an innovation of the year at The Medicine Maker’s 2017 Innovation Awards, and the Cadence BioSMB process system won a 2017 Aspen award for downstream innovation.

Vilcek Prizes Recognize Accomplishments of US Immigrant Scientists

In February, the Vilcek Foundation announced winners of its 2018 prizes in biomedical science. These annual awards call attention to the breadth of immigrant contributions to science in the United States. (In parallel, the foundation also awards prizes for immigrant accomplishments in the arts.) This year’s winners have influenced US biomedical research significantly, from CRISPR-Cas development to the creation of live, three-dimensional (3D) cellular models of the brain. The $100,000 Vilcek Prize was bestowed on Alexander Rudensky. The $50,000 Vilcek Prizes for Creative Promise are awarded to younger immigrants who have demonstrated exceptional promise early in their careers: Polina Anikeeva, Sergiu P. Pasca, and Feng Zhang in 2018.

“The collective discoveries of this year’s prizewinners are truly exceptional,” says foundation chair and CEO Jan Vilcek. “They have wide-ranging implications in both basic and translational science, including novel technologies that until recently were not even within the realm of imagination. They are proof that immigrants push the boundaries of possibility in science and in society.”

Russian-born immunologist Alexander Rudensky is an investigator at Howard Hughes Medical Institute (HHMI) and director of the Ludwig Center at Memorial Sloan-Kettering Cancer Center. Awarded for his work with regulatory T cells (Tregs), Rudensky was born in the former Soviet Union and moved to the United States as a postdoctoral fellow soon after the fall of the Berlin Wall. His recent work has revealed a central role for Tregs in cancer treatment, suggesting that Tregs could help enhance the efficacy of cancer immunotherapy drugs. Rudensky has received other honors including the Crafoord Prize of the Royal Swedish Academy of Sciences and memberships in the American Academy of Arts and Sciences, the National Academy of Sciences, and the National Academy of Medicine.

Polina Anikeeva also was born in the former Soviet Union. She is an associate professor of materials science and engineering as well as associate director of the research laboratory of electronics at Massachusetts Institute for Technology (MIT). Anikeeva has advanced optogenetics, an approach to exploring brain function by using light to control the actions of brain cells in laboratory animals.

Originally from Romania, Sergiu P. Pasca is an assistant professor of psychiatry and behavioral sciences at Stanford University. He uses models of the human brain created through cellular reprogramming technology to explore the biological underpinnings of brain disease. Pasca’s lifelike models of the human brain are paving the way toward improved understanding of disorders such as autism and schizophrenia.

Born in China, Feng Zhang is a professor of neuroscience at MIT’s McGovern Institute for Brain Research and a core institute member of the Broad Institute. He developed tools that have advanced both optogenetics and gene editing. His work has resulted in a growing array of applications including uncovering the genetic underpinnings of diseases, which could lead to gene therapies for curing heritable diseases as well as improving agriculture, among other applications.