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Tackling cancers of the immune system with customized “peptibodies”

letters-451538_1280You've probably heard a lot of  buzz around the concept of "targeted" cancer therapy that kills only tumor cells while sparing healthy cells and tissue. But this goal can be very difficult to achieve. That's in part because, on the surface, cancer cells often look quite like their non-cancerous peers.

The story's a bit different for some cancers of the immune system, however, including B cell lymphomas. Stanford immunologist Ronald Levy, MD, realized decades ago that B cells (the cells that make antibodies to recognize foreign invaders) have a built-in Achilles heel: the unique antibody sequence displayed by each cell and its descendants functioned as a perfect, tumor-specific target to use to kill only cancer cells. I described this finding, and subsequent events that led to the breakthrough lymphoma drug, retuximab in a 2004  Stanford Medicine magazine article about Levy's work.

As I wrote then:

In B cell lymphoma, however, each cancer cell sports an identical bull's-eye in the form of a cell surface receptor meant to recognize foreign invaders. Because the receptors are made up of randomly generated combinations of short protein segments, no non-cancerous cells should have the same marker as the cancerous clones.

Unfortunately, however, this also means that everyone with B cell lymphoma has their own very specific "brand" of cancerous cells. Optimizing this targeted treatment for individuals meant first identifying the antibody sequence on the B cells that make up the tumor and then generating a second antibody to recognize that sequence and target the cells that carried it for destruction.

Now Levy and former graduate student James Torchia, MD, PhD, have come up with a way to streamline the production of what they've termed "peptibodies" to accomplish the same goal. They published their technique this week in the Proceedings of the National Academy of Sciences.

As Levy explained to me:

It is a challenge to generate custom made antibodies for each individual with lymphoma. James came up with an alternative strategy to accomplish the same goal in a process that's fast, scalable and can be easily automated.

Torchia, who is now a medical resident at Massachusetts General Hospital, relied on the fact that human antibodies are shaped roughly like the letter "Y". The vertical trunk of the letter doesn't change from cell to cell, and it serves to cue other cells and components of the immune system to jump into action when the antibody binds to a threat. The arms and tips of the Y, on the other hand, are unique to each B cell, and could serve as a highly specific target for anti-tumor therapies for cancerous B cells.

He devised a way to quickly screen libraries of millions or billions of small protein pieces called peptides and pluck out the one or two that specifically bind to the antibody on the cancerous B cell. He then chemically linked this tumor-specific peptide to the non-variable antibody "trunk" of the Y to come up with a personalized therapy for B cell lymphoma.

As Torchia explained:

We’ve designed a molecule that resembles an antibody and has many of its biological properties but whose binding domain is a small synthetic peptide that can be produced rapidly and relatively inexpensively by automated peptide synthesis, a widespread technology.  We then “snap” this customized peptide on to the pre-made biologic portion which can be mass produced.  This is the “modular”, or semi-synthetic, design that allows for more practical customization for each patient.

Because the peptibodies are smaller than full-sized antibodies, they penetrate more deeply into tissues. It's also possible to attach multiple peptides to the antibody portion to allow faster and tighter binding to the cancer cells.

Using this technique, Levy and Torchia were able to kill B cell lymphoma cells growing in a dish. They were also able to eliminate human lymphoma cells in a mouse model of the disease.

Although the peptibodies have not yet been tested in humans, researchers are hopeful that they may be a way to one day bring truly personalized therapies to patients with B cell lymphomas.

Previously: Training the immune system to attack cancer throughout the body: A new clinical trial at Stanford Stanford’s Ronald Levy offers peek at future of cancer therapy  and Stanford Medicine to join $250 million Parker Institute for Cancer Immunotherapy 
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