Chemists at The Scripps Research Institute (TSRI) have devised a new technique for connecting drug molecules to antibodies to make advanced therapies.

These advanced therapies, also called antibody-drug conjugates or ADCs, are the basis of new therapies on the market that use the target-recognizing ability of antibodies to deliver drug payloads to specific cell types—for example, to deliver toxic chemotherapy drugs to cancer cells while sparing most healthy cells. The new technique allows drug developers to forge more stable conjugates than are possible with current methods.

Carloss_Barbas_Scripp
Carloss Barbas, Scripp

Better therapies less likely to fail
“A more stable linkage between the drug molecule and the antibody means a better therapy—the toxic drug is less likely to fall off the antibody before it’s delivered to the target,” explained Carlos F. Barbas III, the Janet and Keith Kellogg II Chair at TSRI. Barbas and two members of his laboratory, Research Associates Narihiro Toda and Shigehiro Asano, report the finding in the chemistry journalAngewandte Chemie, where their paper was published recently online ahead of print and selected as a “hot” contribution.

MabPlex
 

Limitations to a Popular Approach
The new method for making more stable antibody-drug conjugates comes as the first generation of these powerful therapies are entering the market. Two such conjugates are now in clinical use. Brentuximab vedotin(Adcetris®, Seattle Genetics/Takeda/Millennium), approved by the FDA in 2011, has shown powerful effects in clinical trials against otherwise treatment-resistant lymphomas. It uses an antibody to deliver the cell-killing compound monomethyl auristatin E to cells that bear the CD30 receptor, a major marker of lymphoma. The other conjugate, ado-trastuzumab emtansine (Kadcyla®, Genentech/Roche), approved just this year for metastatic breast cancer, delivers the toxic compound mertansine to breast cancer cells that express the receptor HER2.

The success of these antibody-drug conjugates and the broad potential of the technology have made them popular with drug companies, particularly those trying to develop new anticancer medicines. “The current development pipeline is full of antibody-drug conjugates,” Barbas notes.

Yet the chemical method that has been used to make these conjugates has significant limitations. The method involves the use of compounds derived from maleimide, which can be easily added to small drug molecules. The maleimide molecule acts as a linker or bridge, making strong bonds withcysteine amino acids that can be engineered into an antibody protein. In this way, a single antibody protein can be tagged with one or more maleimide-containing drug molecules. The main problem is that these maleimide-to-cysteine linkages are susceptible to several forms of degradation in the bloodstream. When such a cut occurs, the disconnected payload drug-molecule—typically a highly toxic compound—is liable to cause unwanted collateral damage to the body, like a smart bombgone astray. This instability of current maleimide-based conjugates probably accounts for at least some of their considerable toxicity.

A more stable linkage would mean less toxicity and higher efficacy for antibody-drug conjugates, and for the past several years research chemistry laboratories around the world have been looking for a way to achieve this.

Improved Linkages
Now Barbas and his colleagues appear to have found one in the form of a novel Thiol-Click reaction. In their new paper, they have described a way to make improved linkages using compounds based on methylsulfonyl-substituted heterocycles instead of maleimides. “This method turns out to enable more stable linkages to an antibody protein, as well as more specific linkages, so the drug attaches to the right place on the right protein,” Barbas explained.

Coincident with the report of the new linking compounds in Angewandte Chemie, the chemical supplier Sigma-Aldrich Corporation will begin selling the compounds, so that pharmaceutical companies can start working with them to make more stable antibody-drug conjugates. Under a recent agreement, Sigma-Aldrich markets new chemical reagents from Barbas’s and several other TSRI laboratories as soon as the papers describing them are released.

“Improved antibody–drug conjugate technologies are a top-priority research area in the pharmaceutical industry and exactly the type of fundamental research issue that our partnership with Scripps will continue to address,” said Amanda Halford, vice president of academic research at Sigma-Aldrich.

Although linking drug molecules to target-homing antibodies is the best-known therapeutic application of the new method, Barbas emphasized its broad relevance. “It should be useful for many types of protein conjugation,” he noted. These include the conjugation of proteins to fluorescent beacon molecules for laboratory experiments, as well as the linkage of drug compounds to polyethylene glycol molecules — pegylation — to slow their clearance from the body and thus keep them working longer.

Developing multiple commercial relationships
TSRI approached Sigma-Aldrich to eliminate the delay between the invention of novel reagents and reliable, widespread access to those reagents for the translational research community. “The hurdles from bench to clinic, what the National Institute of Health or NIH calls the valley of death, are proving difficult to surmount, leaving numbers of potential therapeutic ideas trapped inside university doors. To clear these hurdles, it’s critical to open a myriad of novel technologies, such as these from TSRI, to the whole translational research community,” said Amanda Halford, Vice President, Academic Research at Sigma-Aldrich.

This is not the first agreement signed by The Scripps Research Institute. Following recent agreements with Janssen Pharmaceuticals and Bristol-Myers Squibb, this is the third major deal in our new targeted partnership stals and Bristol-Myers Squibb,” said Scott Forrest, Vice President of Business Development at TSRI. “These multi-lab, multi-year alliances fund research and infrastructure in areas of mutual interest, creating a great opportunity for moving innovations into the marketplace. TSRI partners with Sigma-Aldrich to accelerate the commercialization of new research tools for the scientific community.”

For more information:
Toda N, Asano S, Barbas III CF. Rapid, Stable, Chemoselective Labeling of Thiols with Julia- Kocieński-Like Reagents: A Serum-Stable Alternative to Maleimide-Based Protein Conjugation.Angew Chem Int Ed Engl. 2013 Oct 2. doi: 10.1002/anie.201306241. [Epub ahead of print] [Article][PubMed][Abstract]