June 9, 2013 | by Wayne Lewis
As City of Hope celebrates its 100th anniversary, we offer a four-part interview with Art Riggs, Ph.D., chair of the Department of Diabetes and Metabolic Diseases Research. Many of City of Hope’s best-known breakthroughs came through his lab. In this series, he casts an eye back to some of his greatest scientific contributions — and forward to the advances on the horizon.
In Part 3, Riggs talks about his work that led to monoclonal antibodies. These engineered human proteins are the basis for a host of lifesaving cancer drugs.
In the early ‘80s, you and then-City of Hope postdoctoral fellow Shmuel Cabilly, Ph.D., worked with the folks at Genentech and came up with this platform for monoclonal antibodies. Before that point, there was a sense that antibodies could be helpful as therapies, but they were mouse antibodies. The hinge-point there is that you were able to trick bacteria into manufacturing humanized antibodies. How did you start on that project?
The basic idea was a little more general than that.
At that time, [scientist] Herb Boyer and [businessman] Bob Swanson [of Genentech] asked me to work on synthetic growth hormone and I said, “What I want to work on are antibodies.” I thought — and ultimately convinced them — that the recombinant DNA technology could be used to improve antibodies.
|Art Riggs on the influence of science fiction:|
“The main thing, the starting point, is that I love to read. When I was in sixth or seventh grade, I would ride my bicycle down to a library, and somehow I discovered science fiction books. I think the first one may have been Ray Bradbury. I read it and was just fascinated.
“In science fiction, once you accept certain principles, then everything else follows according to more-or-less scientific principles. You have to accept that you can go faster than the speed of light and that sort of thing, so there are a few unrealistic assumptions.
“I would separate it from science fantasy. I like science fiction. So that is real science, space men out there finding and exploring new planets. I don’t read much science fiction anymore but I still occasionally do. And it’s still very interesting.
“I’m disappointed that I never quite made it as a space-traveling scientist or a space cadet. But in my field, I’ve been able to do things that are just as exciting. When I sit back and think about it, I just continue to be amazed at what the field has done in general and that I’ve been able to be part of it. It’s absolutely incredible.”
That was the basic idea. I came up with a fairly long list of how antibodies could be improved. It wasn’t essential that they be made in bacteria. It was that we could cut and splice the heavy and light chains, and remove the constant regions, and shuffle variable regions, and basically do what’s being done now rather efficiently.
It’s getting better and better. It’s still a very active field. It has taken 30 years, but what I suggested in 1980 has pretty much proved to be true. Antibodies can be greatly improved by using recombinant DNA technology. And it’s still developing.
The key thing that we did was we cloned the genes for antibodies. We did clone them into bacteria. We characterized those genes. And then we did actually very correctly and accurately describe how to switch mouse to human. The recipe book for converting mouse antibodies to human — we were the first to write that.
And when you look at the impact of that, there’s a whole host of cancer drugs that use that as the basis: Herceptin, Rituxan, Avastin and Erbitux. There’s also Humira, which is for arthritis. Did you have the sense for all the therapeutic possibilities of these antibodies at the outset?
The answer is yes. I actually even surprised myself when I went back and looked at that list of potential improvements and new approaches to disease. The whole field is finally getting there.
I had worked in an immunology laboratory as part of my training. I am not an immunologist, but I spent time in a lab where most of the people were doing immunology. It gave me the background. The chemistry, the immunology and the recombinant DNA technology came together and worked out really well.