Shepard, Michael

H. Michael Shepard


Dennis Slamon

Dennis J. Slamon

University of California, Los Angeles

Axel Ullrich

Axel Ullrich

Max Planck Institute of Biochemistry

For their invention of Herceptin, the first monoclonal antibody that blocks a cancer-causing protein, and for its development as a life-saving therapy for women with breast cancer

The 2019 Lasker~DeBakey Clinical Medical Research Award honors three scientists—H. Michael Shepard, Dennis J. Slamon, and Axel Ullrich —who invented Herceptin, the first monoclonal antibody that blocks a cancer-causing protein, and developed it into a life-saving therapy for women with breast cancer. The innovation reduces the risk of recurrence and extends survival time for patients with metastatic as well as early-stage disease. Every year, more than 50,000 women in the US are diagnosed with the type of breast cancer that the drug attacks, and over 2.3 million individuals have received the treatment since it became available. Shepard (now at BetterOutcomes4Cancer) and Ullrich (now at Max Planck Institute of Biochemistry, Martinsried, Germany) conducted their Herceptin investigations at Genentech. Slamon did his at the University of California, Los Angeles (UCLA), where he continues to work.

In the mid 1970s, scientists discovered that genes within our own bodies can trigger cancer. This revelation sparked the idea that stifling the activities of such oncogenes might thwart the trouble they instigate. This approach—in which a therapy would fixate on molecules that dwell specifically in cancer cells and also drive malignancy—held great appeal. Such a targeted strategy might avoid many of the harsh side effects associated with chemotherapy while striking the source of the affliction.

They saw HER standing there

Prominent among known oncogenes were several that encode overzealous versions of growth factors and the receptors that sense them. The receptors, which lie across the cell membrane, receive signals from the external environment and then relay them inside to spur proliferation. Ullrich was particularly interested in a subgroup of these proteins—the tyrosine kinase receptors—and he wanted to uncover previously unknown members of this molecular family in humans.

In 1985, Ullrich, Arthur Levinson (also at Genentech), and colleagues found a gene whose sequence resembles that of the human epidermal growth factor receptor (EGFR or HER1) and the chicken oncogene v-erbB. They named it HER2human EGF receptor 2—because of this similarity. Its sequence and location on the chromosome suggested that it might be the human version of neu, a rat oncogene discovered the year before by Robert Weinberg (Massachusetts Institute of Technology). Independently and simultaneously, two other groups, led by Stuart Aaronson (National Cancer Institute) and Tadashi Yamamoto (University of Tokyo), identified HER2 and showed that it was amplified in malignancies from a human breast and a salivary gland.

In the meantime, UCLA oncologist Slamon and, independently, the late William McGuire (University of Texas Medical Center, San Antonio), had been collecting cancer tissues that had been surgically removed for therapeutic reasons and checking whether established oncogenes were firing excessively in them. Ullrich, with his tantalizing gene, and Slamon, with his human tumor library, connected. In 1987, they reported that almost 30% of 189 breast cancer samples contained more than one copy of the HER2 gene. Analysis of health records for many of the patients represented in the study revealed that women whose tumors carried multiple copies of the gene relapsed more quickly and died sooner than did those whose tumors contained only one copy. Furthermore, the gene amplification better predicted prognosis than did most standard indicators, such as tumor size and hormone receptor status.

These associations were provocative, but numerous previously described proteins appeared on cancer cells yet did not propel tumor formation or progression. To gain candidacy as a therapeutic target, HER2 overabundance would have to cause, not just correlate with, malignancy.

To investigate this issue, Ullrich and postdoctoral fellow Robert Hudziak engineered mouse connective-tissue cells grown in laboratory culture dishes to produce extra HER2 protein. The supplemental HER2 caused the cells to keep dividing under conditions in which they’d usually stop, a sign of transformation to a cancerous state. The HER2-augmented cells also displayed other evidence of malignancy, and they formed tumors after injection into mice. Because the only difference between the corrupt and well-mannered cells was the amount of HER2, these results indicated that surplus growth factor receptor unbridles normal restraints on replication.

Simultaneously and in parallel, Shepard, in his own lab at Genentech, had landed on HER2 from a different direction. He was probing the mechanisms by which cancer cells evade destruction by a chemical called Tumor Necrosis Factor-α (TNF-α), a component of the body’s immune response. He had found that activation of some tyrosine kinases can curb TNF-α’s lethal potency. Together, he and Ullrich showed that HER2 renders mouse cells resistant to TNF-α’s toxic effects. Perhaps, they reasoned, HER2 promotes aggressive cancers not only by causing growth to run amok, but also by toughening up the cells and endowing them with ways to withstand assaults that normally would kill them.

If excessive quantities of HER2 cause runaway growth and protection from the body’s defense system, quashing receptor function might reverse these aberrant behaviors. The part of the protein that resides outside the cell was especially alluring because it was likely to be accessible to a drug. To block HER2 stimulation, the researchers wanted to develop a compound that would bind to this exposed portion and impede incoming signals. They sought monoclonal antibodies to serve that purpose.

HER promise revealed

The Genentech scientists made a collection of monoclonal antibodies in mice and zeroed in on one that inhibited growth of several breast cancer cell lines. Crucially, it had this effect only on cell lines that overproduce HER2 protein. Furthermore, it sensitized these tumor cells to killing by TNF-α. The top pick antibody, dubbed 4D5, did not bind to HER2’s relative, the human EGF receptor—an important characteristic, as a successful drug must not interfere with activities of healthy cells. These observations suggested that a 4D5-based treatment would foil only HER2-overexpressing cells.

Even if 4D5 could, in principle, crush tumor growth in people’s bodies, a significant hurdle remained. Because it came from mice, the human immune system would deem it “foreign” and destroy it. To design an antibody that would not stir such an inflammatory reaction, Paul Carter, working with Shepard, aimed to retain the bare minimum of 4D5—only the part that binds HER2—and replace the rest with human antibody sequences. In 1992, the team reported that one of these “humanized” antibodies bound HER2 three times more tightly than 4D5 and blocked proliferation of a HER2-overexpressing breast cancer cell line as efficiently.

Despite these auspicious results, hesitation lurked among Genentech’s decision makers. The company had pursued other potential cancer drugs that had not panned out. Furthermore, many experts were skeptical that monoclonal antibodies would prove therapeutically useful against cancer, especially for solid rather than blood malignancies—in part because scientists doubted that these agents would penetrate the tumors. To bolster the case for clinical pursuit, Shepard and Slamon performed numerous studies. They showed, for instance, that radioactive-tagged mouse antibody—a single dose, so it would not elicit a strong immune response—accumulated in tumors, but only in those of women with cancers that overproduced HER2. This encouraging observation energized the team, as did the patients’ willingness to participate even though they would not benefit and might suffer unknown consequences. Such generosity repeated itself at numerous steps of the enterprise.

During this period, the investigators also collected data that would help guide clinical deployment of the potential drug. Using human breast cancer cells grown in the lab, Slamon and colleagues explored how best to combine the antibody with standard chemotherapy regimens. Genentech scientists and Slamon also developed diagnostic tests to identify women with HER2-overexpressing (HER2+) breast cancers.

Troublemaker transformed into target

The company decided to move forward, and clinical trials began on women with metastatic HER2+ breast cancer. By 1998, the data were strong enough that the humanized monoclonal antibody—now called trastuzumab (brand name, Herceptin)—gained approval by the U.S. Food and Drug Administration (FDA).

In 2001, Slamon and colleagues published those results. A large, randomized study on women with progressive, HER2+ breast cancer revealed that the addition of Herceptin to chemotherapy stalled disease progression, reduced the one-year death rate from 33 percent to 22 percent, and extended overall survival. Subsequent trials on early-stage, HER2+ breast cancer showed that Herceptin also improves outcomes in that setting, for which it was FDA-approved in 2006 (see Figure).

Breast cancer data chart

Beating back breast cancer
Women with early-stage (left) or metastatic (right) HER2+ breast cancer were treated with either Herceptin plus chemotherapy or chemotherapy alone. The percentage of women with early-stage breast cancer who were alive and free of disease four years after beginning the trial was significantly higher if they received Herceptin (85.3 %) than if they did not (67.1 %). The percentage of women whose metastatic disease had not progressed 15 months after beginning the trial was significantly higher if they received Herceptin (~17.5%) than if they did not (~3%).

Herceptin is now a standard therapy for HER2+ breast cancers. Researchers have continued to investigate HER2, and additional antibodies that target it have reached the market. For instance, a drug called pertuzumab differs from Herceptin in the region of HER2 that it binds and its mechanism of action. A 2015 review reported that overall survival of women with metastatic HER2+ disease who received chemotherapy plus pertuzumab and Herceptin was more than 4.5 years. In 2001, life expectancy for women with that diagnosis was 1.5 years.

The impact of Herceptin’s development reaches beyond breast cancer by establishing that monoclonal antibodies can indeed combat solid tumors. Furthermore, the innovation offers a new model for personalized medicine by deploying a diagnostic test that identifies the most appropriate patients to treat with a particular intervention. By uncovering and exploiting the molecular pathology of a devastating disease, Shepard, Slamon, and Ullrich conceived and executed a new blueprint for drug discovery that has already bestowed tens of thousands of women with time and quality of life.

by Evelyn Strauss

Key Publications on Herceptin – Its Invention and Clinical Development

Coussens, L., Yang-Feng, T.L., Liao, Y.-C., Chen, E., Gray, A., McGrath, J., Seeburg, P.H., Libermann, T.A., Schlessinger J., Francke, U., Levinson, A., and Ullrich, A. (1985). Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science. 230, 1132-1139.

Hudziak, R.M., Schlessinger, J., and Ullrich, A. (1987). Increased expression of the putative growth factor receptor p185-HER2 causes transformation and tumorigenesis in NIH 3T3 cells. Proc. Natl. Acad. Sci. 84, 7159-7163.

Slamon, D.J., Clark, G.M., Wong, S.G., Levin, W.J., Ullrich, A., and McGuire, W.L. (1987). Human breast cancer: correlation of relapse and survival with amplification of the HER2 protooncogene. Science. 235, 177-182.

Hudziak, R.M., Lewis, G.D., Shalaby, M.R., Eessalu, T.E., Aggarwal, B.B., Ullrich, A., and Shepard, H.M. (1988). Amplified expression of the HER2/ERBB2 oncogene induces resistance to tumor necrosis factor-alpha in NIH 3T3 cells. Proc. Natl. Acad. Sci. USA. 85, 5102-5106.

Slamon, D.J., Godolphin, W., Jones, L.A., Holt, J.A., Wong, S.G., Keith, D.E., Levin, W.J., Stuart, S.G., Udove, J., Ullrich, A., and Press, M.F. (1989). Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science, 244, 707-712.

Hudziak, R.M., Lewis, G.D., Winget, M., Fendly, B.M., Shepard, H.M., and Ullrich, A. (1989). p185HER2 Monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol. Cell. Biol. 9, 1165-1172.

Shepard, H.M., Lewis, G.D., Sarup, J.C., Fendly, B.M., Maneval, D., Mordenti, J., Figari, I., Kotts, C.F., Palladino, Jr., M.A., Ullrich, A., and Slamon, D. (1991). Monoclonal antibody therapy of human cancer: taking the HER2 protooncogene to the clinic. J. Clin. Immunol. 11, 117-127.

Carter, P., Presta, L., Gorman, C.M., Ridgeway, J.B., Henner, D., Wong, W.L., Rowland, A.M., Kotts, C., Carver, M.E., and Shepard, H.M. (1992). Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc. Natl. Acad. Sci. USA. 89, 4285-4289.

Pegram, M.D., Lipton, A., Hayes, D.F., Weber, B.L., Baselga, J.M., Tripathy, D., Baly, D., Baughman, S.A., Twaddell, T., Glaspy, J.A., and Slamon, D.J. (1998). Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185 HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J. Clin. Oncol. 16, 2659-2671.

Slamon, D.J., Leyland-Jones, B., Shak, S., Fuchs, H., Paton, V., Bajamonde, A., Fleming, T., Eiermann, W., Woldter, J., Pegram, M., Baselga, J., and Norton, L. (2001). Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783-792.

Shepard, H.M., Jin, P., Slamon, D.J., Pirot, Z., and Maneval, D.C. (2008). Herceptin. In Therapeutic Antibodies. Handbook of Experimental Pharmacology. Edited by Y. Chernajovsky and A. Nissim, Springer-Verlag, Berlin, Heidelberg. pp. 183-219.

Seurat’s Dots: A Shot Heard ‘Round the Art World

Seurat’s Dots: A Shot Heard ‘Round the Art World

How the color theories of a chemist have ricocheted across centuries of artistic and scientific imagination.

Award presentation by Michael Brown

Each year 250,000 American women are diagnosed with breast cancer. Twenty percent are caused by extra copies of a gene called HER2. Until recently the 50,000 women with HER2-positive breast cancer had a terrible prognosis. Today the finding of HER2 is good news. When a breast biopsy is HER2 positive and the cancer has not advanced beyond regional lymph nodes, that woman has a 90% chance of being tumor-free for at least 3 years and likely forever. These cures come from an antibody called Herceptin that targets HER2. When Herceptin was approved in 1998 it was the first monoclonal antibody against an oncogene. This single drug changed our entire approach to cancer therapy. It emerged from the work of 3 scientists: Axel Ullrich and Michael Shepard of Genentech, and Dennis Slamon of UCLA.

A Lasker Award for cancer is appropriate because the invention of Herceptin can be traced to our patron saint Mary Lasker. Throughout the 1960’s Mary stalked the lobbies of Congress and the White House advocating fiercely for cancer research. Her lobbying bore fruit in 1971 when President Nixon launched the War on Cancer, and Congress appropriated 1.6 billion 1971 dollars.

Mary’s timing was perfect. Scientists were learning how to manipulate DNA, and now they could focus their methods on cancer. Soon they uncovered the universal cause of cancer—Rogue Genes Gone Wild. Every cell has genes that tell it when to grow and when to rest. If these genes don’t behave themselves, they cause cancer. We call them oncogenes. Cancer is triggered when growth-promoting oncogenes become overactive, or when growth-retarding oncogenes release the brakes.

The HER2 oncogene was discovered in 1985 by Axel Ullrich, a young scientist at a young company called Genentech. Genentech was founded in 1976 in a vacant warehouse in a rundown industrial district called South San Francisco. Coincidentally, 1976 was also the year that Mike Bishop and Harold Varmus discovered the first cellular oncogene—also in San Francisco, but in a more genteel neighborhood.

Axel Ullrich was a big gene hunter. Already, he had bagged the genes for epidermal growth factor (EGF) and its receptor. The EGF receptor is an oncogene. Viruses that carry the gene cause cancer in birds. To find human oncogenes Ullrich hunted for relatives of the EGF receptor gene. He discovered a relative that he prophetically named HER2, which stands for Human EGF Receptor 2. The name was prophetic because he didn’t know that HER2 causes breast cancer. If Ullrich had called it HIM2, it might have caused prostate cancer.

HER2 does not require an external stimulus to cause cell division. The more HER2 in a cell, the more rapidly that cell divides. The link between HER2 and human cancer came when Stuart Aronson at the NIH discovered a human breast cancer that overproduced HER2 because the gene was amplified. Gene amplification happens when cells divide. Errors in DNA copying cause regions of chromosomes to be duplicated. In most cases the duplication is deleterious to the daughter cell and it dies. If the duplicated region happens to contain a growth-promoting oncogene, that cell divides more rapidly than its neighbors. Soon the duplicated region duplicates again and now the cell has 4 copies, then 8, then 16. As the copies multiply, the cells become more malignant.

Dennis Slamon entered the picture in 1987. Stimulated by HER2 amplification in cancers he journeyed to San Antonio in the great State of Texas. There, William McGuire had assembled a bank of tissue from breast cancers. Slamon obtained a DNA probe from Ullrich and he used it to demonstrate amplification of the HER2 gene in 30 percent of breast cancers. He found that patients with HER2 amplification had a much worse prognosis than the other cancer patients. Sixty percent died within 3 years.

At this point our third honoree, Michael Shepard, emerged. He, too, was a scientist at Genentech. His experiments with cancer cells convinced him that overexpression of HER2 causes drug resistance so he took an aggressive approach. In 1989 Shepard and Ullrich announced that they had produced a mouse monoclonal antibody that binds to the part of HER2 that is exposed on the cell surface. The antibody blocked the growth of human breast cancer cells that had HER2 amplification. The mouse antibody was called 4D5. It eventually became Herceptin.

Mouse antibodies cannot be used in humans because humans reject them as foreign. To convert 4D5 into a drug, Shepard took the bold step of humanizing it. He made mutations in the antibody that made it resemble a human antibody. The first humanized antibody was produced by Greg Winter in England, but no one else had done it successfully. Shepard humanized 4D5 and it became Herceptin.

Slamon proposed to Genentech that he should lead clinical trials of Herceptin in women with Her-2 positive breast cancer. There was much opposition in the company. Would a humanized antibody actually work in people? Why develop a drug that would be given to only 20 percent of women with breast cancer? With such a limited market, would the drug be profitable? Shouldn’t we develop a drug that cures all women? Fortunately, Slamon, Ullrich and Shepard prevailed, and the trials were successful. The FDA approved Herceptin in 1998.

In the initial trials Herceptin was given to women whose cancer had metastasized to remote locations. Herceptin delayed progression but there were no cures. Genentech then developed a second antibody called pertuzumab that binds to a different region of the HER2 protein. The combination of Herceptin and pertuzumab plus an old-fashioned cancer poison produces dramatic results. When a breast biopsy shows HER2 positive cancer the combination treatment is given either before or after local surgery. After 3 years 93 percent of women have no detectable tumor and they appear to be cured even when the tumor had spread to regional lymph nodes. Even when the tumor has metastasized to distant sites the Herceptin pertuzumab combination blocks tumor progression for an average of 5 years compared with one-and-a-half years before Herceptin.

Herceptin broke new ground in four respects. First, it validated antibody humanization. Second, it proved that cancer can be cured by antibodies against proteins produced by oncogenes. Third, it showed the benefit of treating subgroups of cancer patients, thereby ushering in precision medicine. Fourth, it established that companies can make a profit on a drug that is restricted to a subgroup. This encouraged other companies to develop drugs targeted at subgroups

It is no accident that Herceptin was developed by Genentech. This is the second Lasker Clinical Award to Genentech scientists—the first went to Napoleon Ferrara for Avastin, an antibody that was also developed for cancer. Who brought cancer to Genentech? Arthur Levinson, an early Genentech scientist, trained with Mike Bishop and he knew a lot about oncogenes. Levinson was head of research at Genentech during development of Herceptin and Avastin, and his influence was profound. Genentech also deserves plaudits for publishing its findings. Most companies keep their work secret until the task is done. Ullrich and Shepard published papers at each step—like Babe Ruth pointing to right field, they told the world what they were going to do, and they did it. Another shot heard round the world.

Finally, I draw attention to the following fact: this triumph came from a collaboration between an academic physician-scientist and a drug company. Neither party could have succeeded without the other. Pharma needs physicians, and physicians need pharma. And yet physicians who work with pharma are under suspicion. They are assumed to have conflicts of interest and they must confess their sins in public mea culpas. Thank goodness for physicians like Dennis Slamon and pharmaceutical scientists like Axel Ullrich and Michael Shepard who collaborate to bring science to the bedside. The two movements helped relieve women from severe burdens. Ullrich, Slamon and Shepard are worthy recipients of the Mary and Albert Lasker Clinical Award.

Acceptance remarks

2019 Basic Award video