Genentech’s New ADC Platform Has Much Potential, but Is Yet to Be Tested on Humans

by: Ohad Hammer

On June 18th, Seattle Genetics (SGEN) announced it had received a milestone payment from Genentech (DNA) after the latter filed an IND (Investigational New Drug) application for an antibody-drug conjugate [ADC] powered by Seattle Genetics’ technology.  Intriguingly, there was no additional data about the new agent, nor was there any official announcement from Genentech.

An article that will be published in this month’s issue of Nature Biotechnology may shed some light on the identity of the new ADC and the technology it utilizes. Based on this article, the new agent will not be based solely on the familiar Seattle Genetics’ ADC technology, but will also utilize a next generation platform with potentially disruptive implications.

The article, titled “Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index”, describes a new technique for designing and constructing ADCs that could be amenable to a wide range of antibodies and drugs. Generally speaking, the new ADC, termed TDC (THIOMAB-drug conjugate), was designed to allow a more controlled way of ADC construction, through means of genetic engineering and chemistry. TDCs differ from the traditional ADCs mainly in terms of the number of drug molecules per antibody and homogeneity. While traditional ADCs are heterogeneous in terms of number of drug molecules per antibody and their distribution across the antibody, in TDCs it is possible to determine in advance the exact number of drug molecules per antibody and their positions.

In order to validate the new platform, the investigators compared a TDC targeted against MUC16 with a traditional ADC which binds the same target. The results presented in the article indeed imply that TDCs may be advantageous over traditional ADCs because they seem to cause milder side effects, and could thus be given at higher doses. When evaluated in animal models, the anti-MUC16 TDC was given at doses that resulted in higher amounts of overall drug without increasing toxicity. This platform allegedly addresses one of the most notorious pitfalls of many ADCs, which is the narrow gap between the effective dose and the toxic dose. Any increase in this gap, termed therapeutic window, adds to the value of a therapeutic candidate.

Genentech’s TDC platform may represent a true advance in the ADC field, however, it is not aimed at replacing the existing ADC technologies, but at complementing them. The anti-MUC16 TDC, for instance, employs Seattle Genetics’ proprietary technology. The drug molecule that has been conjugated to the antibody is the same as that of SGN-35, while the linker between the two seems like a variation of Seattle Genetics’ peptide linker.

Investigators left little room for speculation as to Genentech’s plans, which certainly intends to commercialize the new technology. In the article’s discussion section, the authors explain that their platform is the only one which can produce large amounts of homogenous ADCs in a cost efficient manner, a prerequisite for advancing any compound into clinical trials.

From the article it can be inferred that the anti-MUC16 TDC, based on Seattle Genetics’ technology, will be the first TDC to enter the clinic, so it may very well be the agent for which the IND was filed. This is, without a doubt, a huge vote of confidence in Seattle Genetics’ technology, on top of the obvious commercial value.

It is worth mentioning that Genentech’s new platform is amendable to other ADC technologies, such as that of Immunogen’s (NASDAQ:IMGN). In fact, Genentech presented a TDC based on Immunogen’s technology at the recent AACR meeting in April. The authors mentioned additional TDCs that had been evaluated in Genentech’s labs with similar results, therefore, one would expect Genentech to advance additional TDCs based on either Seattle Genetics’ or Immunogen’s technology into clinical trials in the foreseeable future. In particular, a TDC that binds to a prostate cancer related target (TenB2) and also utilizes Seattle Genetics’ technology could also be on its way to the clinic.

It is important to remember that Genentech’s new platform, regardless of its huge potential, has never been evaluated in humans, so it still remains to be seen whether it will live up to its promise. This development is, above all, another testimony for how active and dynamic the ADC market currently is. It also reminds us that novel technologies will continue to emerge and serve as the basis for better antibody-drug conjugates.

Going forward, there will be much more to choose from, with key players working diligently on developing new platforms and improving existing ones. This will make things more interesting (and complicated), as there will be many flavors of ADCs to choose from in terms of the appropriate antibody, conjugation technique, linker and drug. One example might be the new linkers recently disclosed by Immunogen. ADCs that utilize these linkers (termed POL linkers) were shown to be highly effective against multi-drug resistant [MDR] cancers, which are inherently resistant to other ADCs. This may open the possibility to target tumors that until now were relatively resistant to Immunogen’s ADCs, such as colorectal cancer.

The next big event in the ADC field will be the disclosure of data from an ongoing phase II trial of T-DM1, another ADC that is being developed by Genentech, based on Immunogen’s technology. Genentech, which has already stated it would publish data from the 100 patient trial at the ASCO Breast Cancer conference early next month, is also expected to announce its decision whether (or not) to promote T-DM1 into a registration phase III trial. Although Genentech said it would make the go/no-go decision in 2008, it may eventually choose to announce it at another occasion, similarl to what happened at this year’s ASCO annual meeting. Most observers predict that the results will justify a phase III trial, which is probably the reason for the recent climb in Immunogen’s share price.

In the meantime, if you are interested in reading more on antibody-drug conjugates and why the field is one of the most exciting places in the biotech industry, you can start here, here and here.

Disclosure: Author is long SGEN and IMGN.