Chemistry students at Indiana University, Bloomington, who listen to Richard D. DiMarchi’s lectures may feel like they are taking Blockbuster 101.

RICHARD DIMARCHI Chemistry professor and former Lilly exec sees promise in pushing biotechnology in a chemical direction. NOAH CHRISTIAN, INDIANA UNIVERSITY

Humalog is an insulin analog, insulin lispro or Lys(28), Pro(29). “The big challenge wasn’t as much the science, although the science was embedded in that, but it was the emotional logic that this shouldn’t happen,” he says of the drug development. Humalog differs from human insulin in that the amino acids at positions 28 and 29 on the insulin -chain are reversed. In DiMarchi’s view, the approval of Humalog “established a precedent that made it more attractive, maybe easier, for subsequent second-generation peptides and proteins to be reviewed and accepted.”

BLOCKBUSTER As group vice president of biotechnology of Lilly Labs Richard DiMarchi played a crucial role in the design of blockbuster drug Humalog [insulin lispro (rDNA origin)]. COURTESY OF RICHARD DIMARCHI

DiMarchi was attracted to recombinant DNA technology because, as he says, it not only permits the production of proteins in large quantities and high purity but because it “was truly a commercial engine.”

But going one step further and applying that technology to produce a peptide different from the native one was an idea that flew in the face of conventional logic. After all, he was told, nature has spent eons optimizing proteins. As a chemist, however, DiMarchi decided to concentrate on pharmacology by optimizing a behavior for which nature had not selected to obtain properties and a behavior that was going to be meaningful to patients.

Within Lilly, he says, “it was a very tough sell.” Part of the hurdle was timing. His idea about optimizing a peptide came after hundreds of millions of dollars had been spent in the 1980s to develop the natural human sequence of insulin. That in turn had led to the first recombinant DNA protein: Humulin.

The recombinant technique had provided a virtually unlimited supply of hormone. Gone was the need to obtain it from slaughtered pigs. “Looking back, [given] the epidemic of type 2 diabetes that has emerged, but for that technology we might be in a stage today where we would be rationing insulin,” DiMarchi says.

“To many within the organization, particularly the nonscientists, they felt this story was complete,” DiMarchi says. “It was a tremendous scientific success, tremendous commercial success.” Many in the company wanted to celebrate Humulin rather than befriend a new idea and new challenge. Some doubted whether changing the amino acid sequence would change the pharmacology in a positive way. The concept of altering the peptide also seemed to raise the specter of increased immunogenicity. The journey Lilly had completed, the move away from porcine insulin to human insulin, had led to a compound with less of a problematic immune response.

“Our hypothesis was it would not be—and in fact it could be less—immunogenic because it had this lesser propensity to aggregate,” he says. Aggregates injected in the subcutaneous tissue increase the propensity for immune response. “Today, we know that this particular insulin is not more immunogenic than native human insulin, yet it provides the convenience, the greater efficacy, and the lesser hypoglycemia when used properly,” he says.

DiMarchi does not see small-molecule conventional drugs and large-biomolecule drugs as being fundamentally different. They are just chemical entities of different sizes. “My thinking was really framed from my chemical training,“ he says.

His exposure to medicinal chemistry has taught him about taking nature’s products and refining them to obtain better drugs with higher potency, higher selectivity, less toxicity, more convenient dosing, oral activity—all facets that could be engineered with chemistry. “You could take penicillin, and you could improve it by making a semisynthetic version and total synthetic analogs,” he says. “This is the history of medicinal chemistry with small molecules.

“But somehow, people have drawn this line that when you got to proteins, you could not take nature’s starting point and bring in chemistry to improve the behaviors,” he says. Humalog demonstrated, in his view, that it is possible to take nature’s 20 amino acids and, by changing the sequence slightly, obtain a better medicine. Now, as a continuation of this approach, Ambrx is pioneering what he terms chemical biotechnology.

As a broad technology platform, “it is biotechnology as we have known it” to do microorganism-directed synthesis with a broader chemical set, he says. The microorganism brings the synthetic diversity that just does not exist in nature’s repertoire.

A crucial concept, in his mind, is having a technique that is also commercially viable. While it was a great success to synthesize insulin chemically—a feat achieved in the mid-1960s on three continents by teams all finishing within a year of one another—it was “commercially irrelevant,” DiMarchi says. It was never going to be possible to make enough material at high enough purity. The moment of commercial viability only arrived with recombinant DNA, when it became possible to manufacture the materials at sufficient commercial scale, purity, and cost.

In DiMarchi’s view, Ambrx’ technology platform takes a similar leap. This new technology opens up the possibility of finding better medicines, he says, expanding on recombinant technologies developed in the past 25 years. Given past experience, “we know we can make them at the end of the day.”

DEVELOP At Eli Lilly, DiMarchi was involved in the discovery and development of several Lilly drugs, including Forteo [teriparatide (rDNA origin)], human parathyroid hormone. COURTESY OF RICHARD DIMARCHI

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