Another non-unanimous PNAS retraction, for potential anti-cancer drug, after company’s method proves unreliable
There’s another non-unanimous retraction in the Proceedings of the National Academy of Sciences (PNAS) this week, and this one involves an anti-tumor antibody that may not be what the authors originally thought it was.
According to the notice for “The antibody zalutumumab inhibits epidermal growth factor receptor signaling by limiting intra- and intermolecular flexibility:”
The undersigned authors wish to note the following: “In our study we employed Protein Tomography (PT), an electron tomography method commercialized by Sidec AB, for structural analysis of proteins. Following our publication, doubts were raised with respect to the validity of Sidec PT, and we therefore conducted an extensive validation study with Sidec AB to determine the fidelity of PT for structural analysis of therapeutic antibodies and antibody–antigen complexes in solution. In two independent double blind experiments, PT was found to be highly unreliable in distinguishing structural features of the molecules and complexes studied. First, approximately 90% of the identified protein density maps could not be interpreted due to complex morphology or low quality. Second, among the remaining objects, a high number of the protein images observed did not match with sample composition resulting in misinterpretation of sample identities. These disappointing results led us to reanalyze our previously acquired PT data in situ using a weighted backprojection reconstruction method with IMOD (1) rather than COMET (2), which also indicated our previous analysis to be unreliable. With the current PT methods, we were thus not able to validate tomograms neither obtained from vitrified proteins in solution nor aldehyde-fixed, stained cells. Therefore the undersigned authors no longer feel confident of the PT data presented in Figs. 3, 4, 5, and S4 of our study. The authors stand behind the supporting biochemical data provided in the manuscript and believe the proposed model to be plausible, the validity of which, however, should be addressed with other methods. We found it important to notify our colleagues of the specific technical flaws in our publication and apologize for for any inconvenience caused. We hereby retract this manuscript.”
The paper has been cited 25 times, according to Thomson Scientific’s Web of Knowledge.
Just as in last week’s PNAS retraction, not everyone signed. This time, the odd woman out was Anne von Euler, who was apparently at Sidec, the company whose product “found to be highly unreliable” when the researchers tried to repeat the experiments, when the paper was originally published. She is now listed as a member of the department of molecular biology and functional genomics at Stockholm University.
The study’s corresponding author, Paul W.H.I. Parren, is senior vice president and scientific director of Genmab –which last year put its plans to conduct late-stage trials of zalutumumab for squamous cell carcinoma of the head and neck on hold, after failing to find a partner to develop and sell the drug. CEO Jan van de Winkel told Genetic Engineering & Biotechnology News last June:
We have always been focused on ending our investment in zalutumumab so that we can concentrate our resources to progress other high-value programs in our pipeline. The product has shown good results in our clinical studies without any serious adverse effects, and I believe it has therapeutic potential. However, we were committed to taking a decision on the future of the product by the end of June and therefore we will now shelve Zalutumumab but make it available for partnership should the opportunity arise.
We haven’t been able to reach von Euler or Parren for comment, but we’ll update with anything we hear back.
Update, 11:30 a.m. Eastern, 3/22/12: Please see an update with comments from von Euler and Parren.
Hat tip: John Timmer