Adipotide (FTPP): What the Research Shows

Most obesity drugs act on appetite or metabolism. Adipotide was designed to do something blunter: find the blood vessels that feed white fat and destroy them. Developed at MD Anderson Cancer Center in Houston, it reversed obesity in mice and caused rapid weight loss in obese monkeys, along with kidney injury that the researchers described as mild and reversible. Its only human trial started in 2012 and has not published results.

This guide explains where adipotide came from, how its two halves work, what the mouse and monkey studies found, why the kidney findings matter, what happened to the human trial and what to check when sourcing adipotide as a laboratory reagent in Canada.

The idea: blood-vessel “zip codes”

The cells that line blood vessels are not the same everywhere in the body. Vessels in different organs, and in tumours, carry different proteins on their surface, a pattern researchers have called a vascular zip code. In 1996, Renata Pasqualini and Erkki Ruoslahti described a way to read those codes in living animals, called in-vivo phage display. A library of bacterial viruses (phages), each displaying a different short random peptide, is circulated through the bloodstream of a mouse. The phages that stick to the blood vessels of a chosen organ are recovered and sequenced, revealing peptides that home to that organ.

The next step was to make those homing peptides carry a weapon. In a 1999 Nature Medicine paper by Ellerby, Arap, Pasqualini and colleagues, peptides aimed at tumour blood vessels were fused to a synthetic sequence that kills cells from the inside, and the combination showed anti-cancer activity in mice. Peptides built this way are sometimes called “hunter-killer” peptides. At MD Anderson Cancer Center in Houston, Pasqualini and Arap later turned the same approach on fat. The reasoning came from cancer research: like a tumour, white fat depends on its blood supply.

How adipotide is built

Adipotide joins a homing loop that finds fat-tissue blood vessels to a killing domain that destroys them, with two glycines in between. Its published structure is written CKGGRAKDC-GG-D(KLAKLAK)₂.

The homing loop

CKGGRAKDC came out of phage-display screens in mice as a peptide that homes to the blood vessels of white fat. The cysteines at either end are linked by a disulfide bond, which closes the nine residues into a ring. Its partner on the vessel wall turned out to be prohibitin, which the 2004 paper describes as “a multifunctional membrane protein” and which is best known for its role inside mitochondria.

The killing domain

(KLAKLAK)₂ is 14 residues of lysine, leucine and alanine. It is amphipathic: when the chain coils into a helix, the positively charged lysines and the water-repelling leucines and alanines sit on different faces, a design that lets it disrupt membranes. Its designers described it as built “to be nontoxic outside cells, but toxic when internalized into targeted cells” by disrupting mitochondrial membranes, which sets off apoptosis, a form of programmed cell death. Many antimicrobial peptides share this positively charged, amphipathic design; our guide to antimicrobial peptides covers that family.

The killing domain is made entirely of D-amino acids, the mirror images of the L-amino acids in natural proteins. Proteases, the enzymes that normally break peptides down, recognize D-amino acids poorly, so the domain survives longer. Our guide to D-amino acids explains why.

The 2004 mouse study

Mikhail Kolonin, Pasqualini and Arap at MD Anderson, with colleagues at Baylor College of Medicine, published the first adipotide results in Nature Medicine in 2004, under the title “Reversal of obesity by targeted ablation of adipose tissue”. Phage display in mice had turned up CKGGRAKDC as a peptide that homes to white-fat blood vessels. The team identified prohibitin as its receptor and fused the loop to D(KLAKLAK)₂. Aiming the construct at prohibitin “caused ablation of white fat”, and the paper reported “rapid obesity reversal without detectable adverse effects” in obese mice.

MD Anderson’s announcement of the paper added that a month of treatment brought severely obese mice back to a normal body weight, and that follow-up work ruled out poor absorption of food or a loss of appetite as the explanation. The abstract itself gives no percentage figures, so precise mouse weight-loss numbers quoted online should be treated with caution.

The 2011 monkey study

Mouse results often fail to carry over to primates, so the team tested adipotide in spontaneously obese rhesus monkeys. The study, with Barnhart as first author, appeared in Science Translational Medicine in November 2011. Its efficacy work had two parts: a nine-week pilot in four monkeys, two treated and two given saline, and a main study in 15 monkeys, 10 treated and 5 controls, with 28 days of treatment followed by 28 days of recovery. In the pilot, the two treated monkeys lost 15.4% and 20.4% of their body weight. The paper reported that adipotide “induced targeted apoptosis within blood vessels of white adipose tissue”, the same mechanism seen in mice.

Two cautions apply. The groups were small, and the control monkeys also lost some body fat during the study, so the comparison with controls matters more than any single number. The treated monkeys also ate less of their standard biscuit food, and the higher the dose and the greater the weight loss, the less they ate, although they kept eating their enrichment foods. The authors concluded that this most likely reflected feeling full, though they said mild nausea could not be completely ruled out; either way, eating less may have contributed to the weight loss. The paper later drew a published comment, and a reply from the authors, in the same journal.

The kidney signal

The main safety finding in the monkeys involved the kidneys, specifically the proximal tubules. These form the first segment of each nephron’s tubule, and they reclaim glucose, phosphate, potassium and small proteins from filtered fluid. The study reported:

• Dose-dependent rises in serum creatinine at the higher dose levels, which reversed after treatment stopped, without a matching rise in blood urea nitrogen.
• Glucose and protein in the urine, and more kidney epithelial cells shed into it.
• Lower blood levels of phosphorus and potassium.
• Dose-dependent damage to proximal-tubule cells in a separate group of lean monkeys, with signs of regeneration and minimal changes after recovery.
• More urine output, with mild dehydration at the highest dose levels.

Most changes reversed within 28 days of stopping, although one treated monkey in each study still had a slightly raised creatinine level or glucose in its urine. The authors characterized the kidney effects as mild, dose-dependent and reversible. The findings fit the proximal tubule’s job, and they made kidney function a central safety question for any human study.

The human trial and what happened next

In December 2010, MD Anderson licensed the obesity rights to Ablaris Therapeutics, a majority-owned subsidiary of Arrowhead Research; other uses of the platform were licensed to Alvos Therapeutics. In January 2012, Arrowhead announced that the US Food and Drug Administration had cleared a phase 1 trial, to be run by MD Anderson in obese men with castration-resistant prostate cancer. A 2011 report on the program pointed to research suggesting that white fat can promote prostate cancer growth. A phase 1 study’s main job is to test safety rather than effectiveness; our guide to clinical trial phases explains the stages.

1. 1996Pasqualini and Ruoslahti describe in-vivo phage display for finding organ-specific blood-vessel markers.
2. 1999Ellerby, Arap, Pasqualini and colleagues fuse tumour-homing peptides to D(KLAKLAK)₂ and report anti-cancer activity in mice.
3. 2004Kolonin and colleagues identify the fat-vessel loop CKGGRAKDC and its receptor, prohibitin, and report obesity reversal in mice.
4. December 2010MD Anderson licenses the obesity rights to Ablaris Therapeutics, majority-owned by Arrowhead Research.
5. November 2011The rhesus monkey study is published in Science Translational Medicine.
6. January 2012Arrowhead announces FDA clearance for a phase 1 trial at MD Anderson.
7. July 2012The first patient begins treatment, according to Arrowhead.
8. 2014Arrowhead’s annual report describes patient recruitment as ongoing, but says that “internal resources are not being expended” on the program.
9. Since thenNo trial results have been published, and the AdisInsight drug-development database lists the program as discontinued.

We could not find a ClinicalTrials.gov record for the study. Pasqualini and Arap later moved to the University of New Mexico and, in 2018, to Rutgers University in New Jersey.

Later research on prohibitin and fat

Prohibitin turned out to have a partner. In a 2016 JCI Insight paper, Salameh and colleagues, including Kolonin, Pasqualini and Arap, reported that annexin A2 works with prohibitin at the surface of the cells lining fat-tissue blood vessels and of fat cells themselves. Together with the fatty-acid transporter CD36, the two form a complex involved in moving fatty acids into fat tissue. Mice lacking annexin A2 had smaller white fat depots and were slower to gain weight on a high-fat diet. CKGGRAKDC homed poorly to fat in these mice, which suggests the loop’s target depends on the annexin A2 and prohibitin pairing.

One study is often misquoted. In 2015, a Houston team reported that a different hunter-killer peptide, which targets the progenitor cells that give rise to fat cells rather than blood vessels, led obese mice to form beige fat. Adipotide, tested alongside it for comparison, did not affect white fat in those experiments. Claims that adipotide “browns” fat do not come from this work.

Adipotide vs AOD-9604

Adipotide is often listed next to AOD-9604 as a metabolic research peptide, but the two have little in common.

Other metabolic research compounds work through different routes again. MOTS-c is a peptide encoded in mitochondrial DNA, 5-Amino-1MQ is a small-molecule NNMT inhibitor rather than a peptide, and the GLP-1 family acts on gut-hormone receptors. Our guides to AOD-9604, MOTS-c, 5-Amino-1MQ and the GLP-1 peptides cover each one.

What’s established and what isn’t

Sourcing adipotide for research in Canada

Adipotide is harder to make and to verify than most research peptides, because it combines a disulfide-closed loop with a block of D-amino acids. Before ordering, check that:

• The mass is reported as a deconvoluted molecular mass. With eight lysines and an arginine, adipotide carries many positive charges and appears in electrospray mass spectrometry as a ladder of multiply charged ions. See how to read a peptide mass spectrum.
• You know which form the expected mass refers to. The ring-closed (disulfide) form is 2 Da lighter than the open, reduced form, and some catalogue figures include a counter-ion. Ask for the expected mass for your batch and compare.
• You know what was not tested. D- and L-amino acids have identical masses, and routine purity methods may not separate them. Confirming the D-configuration needs chiral analysis.
• The HPLC trace shows a clean main peak. Very basic peptides can tail on reversed-phase columns, which can hide nearby impurities. See how to read an HPLC chromatogram.
• Net peptide content is taken into account. Each basic group can carry a TFA or acetate counter-ion, so the powder is not all peptide. See net peptide content.
• The batch number on the certificate matches your vial, and the peptide is stored cold, dry and dark. See our COA guide and peptide storage guide.

AdipotideProhibitin-targeting peptide (FTPP)View product AOD-9604Growth hormone fragment 177–191View product MOTS-cMitochondrial-derived peptideView product

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