(Nanowerk News) Biologics, a class of therapies derived from living organisms, offer great advantages to patients struggling with challenging diseases and disorders. Treatments based on biologics can boost the immune system to fend off attacks from infection or target specific pathways to block tumor formation.
“These drugs, which have been around for the last 20 years, are doing wonders,” says Amir Erfani, a postdoc in MIT’s Department of Chemical Engineering (ChemE). “They could save millions of people around the world.”
But the unrivaled biological effectiveness comes at a price. They can be difficult to manage, often requiring time-consuming intravenous (IV) infusions in the clinic. Whether for a patient struggling with a life-threatening or lifelong condition, the prospect of spending hours away from home, every few weeks, can prove terrifying.
Now, new work from the MIT team in collaboration with the pharmaceutical company Merck, which funded the research, suggests practical solutions to the difficulties of administering biologic drugs. In a recent paper published in Advanced Health Care Ingredients (“Crystalline Antibody Laden Alginate Particles: A Platform to Enable High Concentration Subcutaneous Antibody Delivery”), these researchers describe a hydrogel platform for delivering monoclonal antibodies (MAB) — a type of biologic — via subcutaneous injection.
Erfani is the lead author of the paper. Co-authors include Jeremy M. Schieferstein, postdoc in ChemE at the time of the study, now senior scientist at Electrophy; Apoorv Shanker, postdoc at ChemE; Paula Hammond, Institute Professor and head of ChemE; and Patrick S. Doyle, Robert T. Haslam (1911) Professor of Chemical Engineering, and researcher at Merck.
“This is an important milestone,” Doyle said. “We are on the way to changing the next generation of medicine with monoclonal antibodies and other types of therapy.”
Antibodies with higher tests
Unlike most conventional drugs which are chemically formulated and consist of small molecules, biologic drugs are large, unruly chains of proteins, sugars and DNA segments genetically engineered from the source of life. These giant organic molecules don’t fit into the kind of neat, compact packaging typically found in synthetic pills or injectable suspensions.
Take the MAB that Erfani and Doyle focused on, called pembrolizumab, or pembro for short. These unique antibodies bind to receptors associated with mediating immune responses against tumor cells, and are used in a variety of sometimes refractory cancers. Pembro is usually given in a dilute solution by IV over several hours to reach the type of concentration needed to be effective. (Merck has patented a formulation of this drug as Keytruda.)
“When you try to concentrate the existing formulation, the viscosity of the molecules grows astronomically,” says Doyle. “At a critical point, they started feeling each other, and the interaction became a kind of paste.” Forced together, pembro molecules become unstable and change their structure, impairing their therapeutic properties.
So Doyle’s research team at the Soft Matter Engineering Group set out to create a version of pembro that could be injected at concentrations high enough to be effective, but in volumes small enough to be administered comfortably and quickly just under the skin (the second preference of most patients and doctors, after swallowing pills). With expertise in flow, microfluidics and pharmaceutical formulations, the lab is well equipped to meet these challenges.
Go with the flow
“MAB is very sticky and smooth, and we need to find a way for the molecules to move freely in the syringe,” said Erfani. “The insight we had was to use hydrogel particles, made from a sugar-based, water-loving biopolymer that provides a comfortable environment in which proteins will be very happy,” said Doyle. “We’ve used these for other applications, and I know if we can make them small enough they can pass through the needle without clogging it.”
The researchers knew from the toxicity literature that their hydrogel capsules would be biocompatible, and would behave in a syringe. “The hydrogel particles are squishy, can roll over each other, and really flow,” said Erfani. It seemed like a clear voyage to incorporate pembro molecules at the right density for a one to two millimeter subcutaneous injection. But, like most techniques, the devil is in the details.
“It’s hard to keep an antibody intact through the manufacturing process, and then make sure it’s biologically effective because it’s well dispersed under the skin,” says Doyle. Any deviation from the precise formulation of pembro integrated into the soft hydrogel capsules can render the MAB ineffective, or worse.
In a series of experiments spanning nearly five years, Doyle’s lab experimented with achieving the right balance of features. Their study relied on a homemade device that expels a biopolymer solution and pembro crystals together first into the air, and then into a bath where they melt into beads.
“We tested many variables in our design space,” said Erfani, including differences in pembro concentrations, and the composition and pH of the polymer solutions. “The goal is not just to develop drugs in our lab, but also to develop processes that can be easily adapted to pharmaceutical manufacturing.” With his previous industry background developing MAB types in a stable crystal structure, Erfani helped push the team across the finish line. “Not only did he bring all this physical chemistry into the process, but he figured out the experimental design and how to execute it,” says Doyle.
The researchers are now putting their pembro formulation through in vivo trials, with the goal of US Food and Drug Administration approval in the next few years. But Doyle and his group had a broader goal for the hydrogel platform they were creating. “We believe this platform is MAB agnostic, which means we can get many different molecules formulated with the right concentration and flowability,” he said. “That’s a big deal.”
Among the possibilities Doyle envisioned was the slow and sustained release of MAB-containing hydrogel particles – think weeks – after injection. Such platforms can accommodate other types of molecules, such as cytokines, to amplify the immune response, or target specific cancer pathways. Hydrogels can also combine two types of drugs that enhance each other’s properties.
Erfani points to the potential social impact of the platform. “Our technology has the possibility to increase the accessibility of care by reducing patient dependence on hospitals,” he said. Replacing IV sessions with fewer one-time injections would free up time in the clinic for more patients, encourage greater adherence, and even lower drug prices, he notes. People may one day give their own injections at home.
Erfani was very excited about the idea of moving more drugs to the platform, including some of the drugs that died early in development. “There are drug companies that give up because they cannot be formulated in a high enough concentration,” he said. “Isn’t it really exciting to reuse a life-saving drug and bring it back to market?”