In 2011, biotechnology startup Arrowhead Research developed a peptidomimetic drug that was capable of inducing rapid weight loss in mice. The drug worked by killing blood vessels, but was specific only to blood vessels in white adipose tissue. Adipotide was approved for phase 1 clinical trials by the FDA, but then Arrowhead Research fell off of the radar completely. What, exactly, is Adipotide and why did Arrowhead Research seemingly abandon its early clinical trials?
Adipotide the Peptide
Adipotide is a peptide (protein) of sequence CKGGRAKDC-GG-D (KLAKLAK) 2 . It belongs to a class of peptides known as petidomimetic. That simply means that Adipotide is a shortened version of a much larger protein, but that it produces similar effects to its larger counterpart.
To understand how Adipotide works, it is necessary to understand what has become known as vascular “ZIP codes.” Researchers at the University of Texas MD Anderson Cancer Center identified specific receptor distributions throughout human vasculature (blood vessels). Some receptors are found in multiple locations, but others are highly limited to specific regions. Those receptors that are limited to specific regions act like ZIP codes, identifying those vascular regions as unique from other vascular regions in the body1 .
One region that contains unique receptors is white adipose tissue, more commonly known as fat. In fat tissue, there is a receptor known as the prohibitin/annexin A2 receptor. Prohibitin is an interesting protein that is coded for in the BRCA1 region of chromosome 17 (the same BRCA1 associated with breast and ovarian cancer). It turns out that prohibitin is a tumor suppressor gene, which means that, when expressed correctly in healthy adults, prohibitin prevents cancer from arising.
Prohibitins have derived their name from the fact that they prohibit cancer growth. As it turns out, they inhibit cancer growth in several different ways, one of which is to prevent blood vessel growth through programmed cell death. Adipotide has similar effects in prohibiting blood vessel growth and is specific to the prohibitin/annexin A2 receptor. This means that Adipotide only prevents growth of blood vessels found in white fat. Without a blood supply, fat cells die and thus weight loss is achieved. Get related reviews at this link.
Studies in both rats and obese monkeys have found that Adipotide causes apoptosis in blood vessels suppling white fat. Apoptosis is a process in which cells die in an ordered, controlled fashion. Experimental animals thus show a marked loss in white adipose tissue and concomitant weight loss2,3 . Additionally, the animal subjects showed improvements in insulin resistance, meaning that they became less prone to diabetes as a result of losing so much adipose tissue.
Thought the hype around Arrowhead Research on Wall Street died back (as was the case with Wall Street and many biotechnology firms), the company has remained strong and continues to investigate the benefits of Adipotide in both obese patients and cancer patients. A phase 1 clinical trial is currently underway at the MD Anderson Cancer Center in Houston. Treatment will involve 39 obese prostate cancer patients and three different dose levels of the drug4 .
1. Blood vessel mapping reveals four new ‘ZIP codes’. at <http://medicalxpress.com/news/2011-10-blood-vessel-reveals-codes.html>
2. Barnhart, K. F. et al. A peptidomimetic targeting white fat causes weight loss and improved insulin resistance in obese monkeys. Sci. Transl. Med.3, 108ra112 (2011).
3. Kolonin, M. G., Saha, P. K., Chan, L., Pasqualini, R. & Arap, W. Reversal of obesity by targeted ablation of adipose tissue. Nat. Med.10, 625-632 (2004).
4. Arrowhead Research Corporation | Adipotide. at <http://www.arrowheadresearch.com/adipotide>