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HER2: Teaching an Old Target New Tricks

It’s all in the target.

The HER2 story shows that a great target can spur development of numerous successful drugs and drive innovation over decades. Products that bind HER2 have been associated with numerous innovations in biotechnology, including mouse antibody humanization, precision medicine, bispecific antibodies, ADCs, biosimilars and ADCC modification.

HER2 had a humble beginning. In the 1980s, researchers discovered that HER2 overexpression was associated with tumor formation. The diagnostic use of HER2 for breast cancer was established in the late ’80s and the stage was set for the finding drugs that might interact with this target. Mouse antibodies were available for study, and showed promise. One of these antibodies was humanized, cutting edge technology at the time, and Herceptin (trastuzumab) was born with commercial approval in 1998. Herceptin works by blocking as specific target from receiving signals that stimulate growth. The combination of a diagnostic test to confirm target presence with a monoclonal antibody treatment was one of the first examples of precision (personalized) medicine.

Another of those early HER2 mouse antibodies had a less straightforward path to commercialization. This second HER2 antibody, didn’t do much– at least by itself. However, Genentech didn’t give up and a cocktail of Pertuzumab, Herceptin and docetaxel showed stronger results. In 2012 the second antibody was approved as Perjeta, providing Genentech with one of the first antibody combination treatments.

Herceptin’s unique market position was further enhanced by development of a subcutaneous formulation of Herceptin reducing the administration time from over an hour to just five minutes. This makes this highly effective anti-tumor agent easier for patients to take and more affordable. The subcutaneous formulation uses recombinant human hyaluronidase to allow for a massive (by injection standards) 5ml dose which can be administered once every three weeks

As a blockbuster antibody with looming IP expiration, Herceptin became a prime target for development of biosimilars. Roche took a novel approach to biosimilar competition, announcing a relationship with an Indian company, Emcure, to manufacture trastuzumab under Roche’s supervision using the Roche process. The resulting product is branded differently than Herceptin: it’s called Herclon and is sold with the Roche logo on the box.  This unique business model with Emcure also covers another Roche antibody product, Rituximab.

Roche’s strategy was probably based on the inevitability of competition as key patents approached expiration and other companies started developing biosimilars.  Roche started with a conventional strategy, suing the Indian company Biocon who was developing a Trastuzumab biosimilar with their partner Mylan. This slowed Biocon down but did not prevent commercialization. Biocon’s partner Mylan filed for FDA approval and on July 13, an advisory panel unanimously recommended approval.  More recently, the pathway to approval of Biocon’s product s has seen setbacks in developed markets with  the FDA announcing the delay of the decision on the product for three months while it reviews “clarifactory” information and a series of high profile, unsuccessful audits of Biocon manufacturing sites. While all this is going on the list of other companies developing a Trastuzumab biosimilar reads like a who’s who list of biotech and includes Amgen, Samsung, Pfizer and Celltrion.

With the long history of Herceptin, it is fitting that one of the first antibody drug conjugates (ADCs) had Trastuzumab as its antibody component. Kadcyla or trastuzumab emtansine TDM-1 was launched in early 2013 through a partnership of Genentech/Roche and Immunogen. One might think that the complexity of connecting an antibody to a toxin would discourage ADC copycats but this does not appear to be the case with several other HER2 ADCs in development and clinical trials.  Given the diversity in range of sites of attachment and number of toxin molecules attached to the antibody in Kadcyla, it seems hard to call these copycat ADCs biosimilars.

There are even more HER2 antibody or antibody-like molecules making their way through the clinic. Macrogenics recently announced favorable results from clinical trials for their HER2 antibody, margetuximab. Their twist is to engineer the Fc region of a HER2 antibody to result in enhanced antibody-dependent cell-mediated cytotoxicity. (This is called ADCC, not to be confused with ADCs.) Lastly, HER2 binding is found in several bispecific antibodies.

BPTC’s bioTRAK® database forecasts that most biotech products in development will be served by 2000-5000L bioreactors and that blockbuster antibodies like Herceptin will be few and far between in the coming years as products targeted to more narrow groups of patients expand in the marketplace.

The HER2 saga demonstrates that a good target combined with clever technical and business planning and a bit of luck can drive the growth of many companies across decades. New technologies will always be important to drive growth in the biotech industry, but the use of HER2 binders over decades shows the value of a great target.

Blog article by: Mike Jenkins