Molecules matter: The difference between small and large molecules

What do patients with diseases like cancer, rheumatoid arthritis (RA), and psoriasis have in common? Thanks to biologics, They all have hope for a cure and treatment with fewer side effects.

Distinct from their counterparts—traditional pill-in-a-bottle small molecules or new chemical entities (NCE)—biologics are a class of larger molecules derived from proteins. 

“When we talk about biologics, we’re typically talking about protein-based therapies,” said Christine Smith, Senior Director, Discovery Center of Emphasis for Protein Therapeutics in St. Louis. “Our portfolio consists of proteins known as monoclonal antibodies (mAb), peptides (very small proteins), and growth factors.”

Some biologics work by copying substances made naturally by the body, such as insulin for diabetics or hormones for people with stunted growth—to help fight disease. Others, such as mAbs, specifically bind to a target therapeutically.

The ability of biologics to replace complex proteins that patients’ bodies lack or to interact with other proteins means they have the potential to meet a wide variety of unmet needs.

According to the U.S. Food and Drug Administration, biological products often represent cutting-edge biomedical research and, in time, may offer the most effective means to treat a variety of medical illnesses and conditions that presently have no other treatments available.

An example of a promising biologic compound is ticilimumab, Pfizer’s first mAb. Ticilimumab is “a general that runs the attack” on a tumor antigen because it binds to the CTLA4 receptor on T-cells, the immune cells that attack foreign bodies, and blocks a brake to allow for continued expansion of T-cells. 

In early trials, 6 out of 6 metastatic melanoma patients treated with the highest dose of ticilimumab are still alive 26 months and counting. The average life expectancy for patients with metastatic melanoma is six months.

Small vs. large

So, what’s the difference between biologics and NCEs? The most profound difference is size.

Biologics are larger and more complex molecules.

“Protein therapeutics are macromolecules that are typically much greater than 1,000 Daltons in molecular weight,” Smith explained. “Because these molecules are so large, they can alter targets that small molecules have a hard time modulating.”

She explained that a receptor on a cell can bind to a molecule called a ligand, and this interaction can contribute to or help to alleviate the diseased state. “If you want to interfere with that interaction, and the receptor is outside the cell, you can choose either a small molecule or biologics approach. A biologic may be more effective at interfering with the protein-to-protein interaction because the biologic is larger and has more surface area. This larger surface area also allows the biologics to be very selective—they will bind to one rector, but not others,” she said.

Biologics specificity means they can treat specific pathways and thus reduce side effects. In the war against disease, using biologics is like using a laser guided missile.

Up for the challenge – Formulation to FDA

Pfizer’s protein scientists aren’t riding off into the sunset yet. Biologics’ size advantage is also one of its shortcomings. Because the body’s natural defenses—cell membranes, skin, lungs, and gut—prevent absorption of proteins as whole entities, our researchers can’t always get to the target or utilize the most convenient delivery route.

“As of today, large molecules cannot modulate any intra-cellular targets, but small molecules can,” Smith said. “All targets must be outside the cell or extra-cellular, on the cell membrane or floating around in circulation.”

Additional challenges with biologics have to do with manufacturing of the protein drug substance, analytical controls for human trials, and the marketplace.

A myriad of factors must be optimized for commercial product production—from stabilization of the molecule for extended shelf life to formulating the substance in commercial form.

“The small molecules in Pfizer’s portfolio requires one main assay that tells us most everything we need to know about the amount of active ingredient and degradants,” said John Ludwig, Executive Director of Pharmaceutical Sciences Biologics. “For a monoclonal antibody, you are talking about a molecular weight of approximately 1,000 Daltons in molecular weight. “Instead of one major assay, scientists in biologics need to run 5 to 6 complex assays, each looking at a different characteristic (e.g., oxidation, aggregation, deamidation), in order to understand the stability profile of the bio-molecule.

“The difficulty is in how one interprets that data to move to the next step of the process that takes 15 to 18 months from CAN to humans,” Ludwig said.

What’s more, even slight alterations in the manufacturing process for biologics, if not properly controlled and analyzed, can result in changes in the product that are hard to detect and could trigger harmful side effects, he added.

Biologics can be quite expensive, too, costing patients and insurance companies thousands of dollars per month, depending on the dose and frequency of treatment.

“Right out of the gate, biologics are more expensive, so you always have cost-of-goods considerations,” Ludwig said. “For example, some therapeutic area product concepts may favor small molecule approaches due to the cost-of-goods concerns with a biologic approach.

Significant progress has been made and continues to be made in the industry to minimize these cost-of-goods issues.”

Another challenge for scientists is the method of administering biologics to patients. Current methods are intravenous, via infusion or sterile liquid into the vein; and subcutaneous, a small gauge needle injects liquid under the skin, for patients who need chronic administration.

“Everyone, including myself, has a phobia of needled,” Ludwig said. “But most patients benefitting from the therapy adapt to it. However, there are instances where patients just can’t do it. If you look at Somavert®, a commercial product for acromegaly, those patients typically have very frequent thick fingers and don’t have a lot of tactile sense and have a very difficult time performing the manipulations needed for reconstitution and self-administration.”

John added that it would be great if we could administer proteins through a non-injectable route.

That’s what our scientists across the globe are focusing on now. Oral administration of protein therapeutics would be the Holy Grail.

Pfizer – “The biotech company”

Looking ahead, the future looks bright both for patients and Pfizer. We’re poised with a diversified portfolio of blockbuster molecules, both small and large.

Biologics represent the fast-growing segment of research and development, with the demand in the United States expected to grow more than 11 percent this year with biologics.

“We estimate that our biologics sales this year will total $1.5 billion, placing us roughly eighth in the worldwide sales rankings,” PGRD President John LaMattina told colleagues during a recent town hall meeting in St. Louis. “We are targeting to triple our biologics revenues.”

Currently, there are about 19 monoclonal antibodies approved and marketed in the United States.

Pfizer’s development portfolio includes treatments and possible cures for cancer, growth disorders, and a “Roto Rooter” plaque buster for patients with heart disease.

Despite the many challenges the teams will have to overcome, both Ludwig and Smith agree it’s an exciting time to be in biologics, and the clinical implications of some of the projects in our portfolio are simply tremendous.