Next-generation cancer drugs move toward clinical use

Cancer drugs known as bispecific antibodies are rapidly advancing. An increasing number are entering clinical trials and treatment settings, while researchers are developing more complex molecules with new capabilities.

According to Nature, over the past five years, the number of bispecific antibodies approved by regulatory agencies worldwide has risen from just three to more than 20.

This progress, combined with advances in protein engineering and artificial intelligence, has fueled efforts to develop multispecific antibodies capable of simultaneously binding to three or more distinct targets.

For example, at the American Association for Cancer Research meeting on cancer drug discovery and development, held in Boston, Massachusetts, at the end of July, researchers presented multispecific antibody-based cancer therapies that could potentially be less toxic to healthy cells, more effective against tumors, and better equipped than conventional drugs to counter cancer’s ability to develop resistance to treatment.

Multifunctional Drugs

Bispecific antibodies were first described more than 50 years ago, but the first therapeutic based on this technology was not approved until 2009.

Part of the delay was due to difficulties in determining how best to manufacture these molecules in the laboratory. The process often resulted in antibodies binding to themselves or to one another, producing large aggregates that appeared as clumps of unwanted material.

“With better tools and resources for protein production, we can envision these molecules and turn them into reality,” researchers say.

Most bispecific antibodies bind both to a protein expressed by cancer cells and to immune cells known as T cells. These molecules, called T-cell engagers, are designed to bring the two cell types into close proximity and stimulate the T cell to attack the cancer cell.

At least 12 T-cell engagers have been approved for the treatment of cancers, including leukemia and myeloma.

Efforts to Reduce Toxicity

There is still considerable room for improvement. Scientists’ growing understanding of proteins and the different types of cells found within tumors is enabling them to design bispecific and multispecific antibodies that can stimulate anti-cancer immune responses more effectively than earlier versions. Researchers are also developing molecular “switches” that prevent a therapy from becoming active until it reaches the appropriate location.

One major concern surrounding these drugs is toxicity. A pharmaceutical company in Cambridge, UK, presented trispecific T-cell engagers designed to target a specific subset of T cells capable of attacking tumors.

This approach could reduce the likelihood that the antibodies will bind to a broad range of T cells, which could otherwise trigger a harmful immune response.

Other strategies focus on improving the ability of multispecific antibodies to distinguish between cancerous and healthy cells. One approach is to engineer antibodies that bind to additional cancer-associated proteins, thereby reducing the likelihood that the treatment will damage healthy tissue.

The growing sophistication of antibody engineering, together with advances in protein production and artificial intelligence, is opening the way to a new generation of cancer therapies that may be able to target tumors more precisely while reducing unwanted effects and overcoming mechanisms of treatment resistance.