Description
PrymaLab · Research Use Only
ACE-031 1mg
A trap, not an agonist, and the programme stopped in 2013
Almost everything else in this catalogue is an agonist. ACE-031 is not. It binds a receptor and turns it on. ACE-031 is the reverse: a piece of a receptor floating free in the circulation, catching the signalling molecules before they arrive. That inversion accounts for everything below.
Specification Table
| Property | Value |
|---|---|
| Compound | ACE-031 |
| Article class | A fusion protein. Not a peptide |
| Construction | The extracellular domain of activin receptor type IIB, fused to a human antibody Fc region |
| Common shorthand | ActRIIB-Fc |
| Mode of action | A ligand trap. It binds signalling molecules before they reach the membrane receptor |
| Reported ligands bound | Myostatin, activins and GDF-11 |
| Selectivity | Low. It binds several members of the same growth factor family |
| Why the Fc is there | Antibody tails give long circulating half life and allow the protein to dimerise |
| Originator | Acceleron Pharma |
| Programme status | Discontinued in 2013 |
| Why it stopped | Nosebleeds and small dilated surface vessels appeared in the trial |
| Proposed explanation | The trap also absorbs BMP-9, which is involved in keeping blood vessels stable |
| Reported trends before stopping | Higher lean mass and bone mineral density, lower fat mass, none statistically significant |
| Vial | 1mg |
| Storage | Sealed at minus 20°C. Do not agitate. Do not freeze reconstituted solution |
What Kind of Molecule Is ACE-031?
ACE-031 is a fusion protein, which means two pieces of protein joined into one chain that does not exist in nature.
The first piece is the part of activin receptor type IIB that normally sits outside the cell and catches ligands. Cut from the membrane it still binds.
The second piece is the Fc region of a human antibody, doing two jobs at once. Antibody Fc regions circulate for weeks rather than minutes, and they pair up, which means the fusion arrives as a dimer carrying two binding sites.
The result is a molecule that soaks up growth factors and does nothing with them.
That is a completely different thing from a peptide agonist, and the difference runs through the handling section as well as the pharmacology. This is a large glycosylated protein produced in cells, not a synthesised chain, and it behaves like an antibody in solution.
Why Does Low Selectivity Matter Here?
The ACE-031 design intent was myostatin. What the ectodomain actually binds is a family.
Activin receptor type IIB is a receptor for several ligands, so an ectodomain built from it catches several ligands, including activins and GDF-11 alongside the intended target.
For a receptor sitting on a membrane, that breadth is ordinary biology and nothing to remark on. For a trap released into the circulation it means everything the receptor could have bound is now being removed from circulation instead.
This is the mirror image of the selectivity problem that appears elsewhere in this catalogue. A non-selective agonist activates several pathways. A non-selective trap silences several at once, and you find out which ones only afterwards.
It also makes attribution harder in a specific way. With an agonist you can sometimes narrow things down with a selective antagonist. With a trap you would need to know which of the absorbed ligands mattered, and the natural experiment of removing one at a time is not available.
What happened in the clinic is the clearest illustration of the problem anyone could ask for.
What Stopped the Programme?
The ACE-031 trial stopped after its second regimen.
Nosebleeds, bleeding gums and small dilated surface vessels.
Campbell and colleagues published the results in 2017, some years after the programme ended, and reported trends toward higher lean mass and bone mineral density and lower fat mass, none of which reached statistical significance.
The explanation that emerged points back at the selectivity question. The trap also absorbs BMP-9, and BMP-9 signalling is part of what keeps blood vessels stable.
There is independent support for that link. People born with loss-of-function variants in the BMP-9 pathway develop vascular malformations and bleeding, which is the same picture the trial produced pharmacologically.
I find this the most interesting thing about the compound, and it is entirely absent from the listings that sell it.
A researcher planning work here should know that the vascular finding is not an unexplained oddity. It is the predicted consequence of a trap that catches more than it was aimed at, and any design should account for the possibility of off-target sequestration rather than assume myostatin is the only thing being removed.
What Should the Certificate Show?
ACE-031 identity, which for a fusion protein means confirming both halves and the junction between them.
The expression system, because a protein produced in mammalian cells and one produced in a bacterial system are different articles with different glycosylation.
Glycosylation profile, or at least a statement that somebody looked at it. Fc function and half life both depend on it.
Purity by size exclusion chromatography rather than only by reverse phase, since aggregation is the failure mode that matters on a dimeric protein.
Aggregate content, as a number rather than as a reassurance.
Endotoxin, with the method named. A protein from a cell culture carries an endotoxin question that a synthetic peptide does not.
Host cell protein and residual DNA, both as figures.
Lot number and manufacturing date.
A certificate written to a synthetic peptide template will list a sequence purity and stop, and none of the fields above will be on it. That is the wrong document for this article.
What Does One Milligram of a Fusion Protein Mean?
One milligram of ACE-031 is far less than one milligram of a peptide, and the gap is larger than most people expect.
An Fc fusion of this kind is a glycosylated dimer somewhere in the region of 75 to 80 kilodaltons, and the exact figure depends on the glycans. Take 78 as a working figure and one milligram is around 13 nanomoles.
For comparison, a 10 milligram vial of a 2000 dalton peptide holds 5 micromoles, which is roughly four hundred times more molecules.
So a 1 milligram vial of this article is a small quantity in molar terms even though the mass sounds ordinary.
Binding stoichiometry makes it smaller again. ACE-031 works by occupying ligand, one binding event at a time, so the useful quantity is set by how much ligand there is rather than by how potent the trap is.
That is a different relationship from an agonist, where a catalytic amount can drive a large response. A trap is consumed by what it catches.
Anyone sizing an experiment should calculate the molar quantity of target ligand present in the system and compare it against the 13 nanomoles in the vial, rather than reasoning from a concentration that worked for a peptide.
Glycosylation adds one more wrinkle, which is that the mass is a distribution rather than a single figure, so the molar calculation is approximate no matter how carefully it is done.
A related point that follows from the trap arithmetic.
Because a trap is consumed by what it binds, the useful working question is not what concentration to reach but how long the trap stays available.
That is a different experimental variable from anything else in this catalogue, and it is one the vial size sets directly.
A design running over days rather than hours needs to account for the trap being used up, and a single vial may not carry it.
Why Was Myostatin a Target at All?
Because of cattle, and then because of mice.
Certain cattle breeds carry a natural loss-of-function variant and are visibly more muscular than their relatives, a phenotype known long before anyone knew the gene.
McPherron and colleagues identified the gene in 1997. Mice lacking it developed dramatically more muscle mass, which established myostatin as a negative regulator of muscle growth.
Later work by the same group showed that a soluble form of the receptor produced a similar effect pharmacologically, which is the direct ancestor of ACE-031.
That is an unusually clean target rationale. A gene, a natural knockout phenotype in two species, a mouse knockout, and a pharmacological reproduction of the phenotype.
It is also a good illustration of the gap between a clean rationale and a working compound.
The genetic evidence concerns removal of one ligand across a whole lifetime. The pharmacological approach removes several ligands intermittently in an adult animal, and those are not the same intervention even when the intended target is the same.
The vascular findings that stopped the clinical programme sit precisely in that gap, and they were not predictable from the genetics because the genetics only ever removed myostatin.
The target itself has not gone away. Other approaches to the same pathway have continued, and some of them narrowed the ligand specificity precisely because of what happened here.
How Should the Vial Be Handled?
Handle it as a protein, because it is one, and protein rules are stricter than peptide rules on every axis.
Sealed lyophilised material holds at minus 20 degrees Celsius or below, dark and dry.
Bring the vial to ambient temperature before opening, then reconstitute by running the diluent down the wall and letting the cake dissolve on its own.
Do not vortex ACE-031, do not shake it, and do not pipette it vigorously. A dimeric protein at an air-liquid interface unfolds and aggregates, and the damage is invisible.
Do not freeze the reconstituted solution. Freeze-thaw is the most reliable way to destroy a protein preparation.
Aliquot on first reconstitution and keep working stocks refrigerated for short periods rather than frozen.
Use low-binding consumables at every step. Adsorption on a protein at assay concentrations is substantial.
Run size exclusion chromatography on anything held more than a few days, and keep the trace.
Record lot, expression system, aggregate content if measured, diluent, storage temperature and reconstitution date.
Expression system belongs on that list. It changes what the molecule is, which is a different thing from how it was made.
Published Literature
Selected references on the clinical trial that ended the programme, on animal work with the same construct and on protein storage generally.
- Campbell C, McMillan HJ, Mah JK, Tarnopolsky M, Selby K, McClure T, et al. Muscle and Nerve. 2017;55(4):458-464. DOI: 10.1002/mus.25268
- Lee SJ, McPherron AC. Proceedings of the National Academy of Sciences. 2001;98(16):9306-9311. DOI: 10.1073/pnas.151270098
- McPherron AC, Lawler AM, Lee SJ. Nature. 1997;387(6628):83-90. DOI: 10.1038/387083a0
- Manning MC, Chou DK, Murphy BM, Payne RW, Katayama DS. Pharmaceutical Research. 2010;27(4):544-575. DOI: 10.1007/s11095-009-0045-6
Frequently Asked Questions
Is ACE-031 a peptide?
No. ACE-031 is a fusion protein, made from the extracellular part of activin receptor type IIB joined to a human antibody Fc region. Nothing about it is a synthesised peptide chain.
What does a ligand trap do?
It binds signalling molecules in the circulation before they reach the receptor on the cell surface. It absorbs a signal rather than sending one.
Why is the antibody Fc there?
Two reasons. Antibody tails circulate for weeks rather than minutes, and they pair up, so the fusion arrives as a dimer with two binding sites.
What does it bind?
Myostatin, activins and GDF-11 among others. The receptor it was built from binds a family of ligands, so the trap catches that family.
Why does low selectivity matter more for a trap?
A non-selective agonist activates several pathways. A non-selective trap silences several, and you cannot narrow it down with an antagonist the way you can with an agonist.
When did the programme stop?
In 2013. The trial was halted after the second regimen and the developer discontinued clinical development.
What findings stopped it?
Nosebleeds, bleeding gums and small dilated surface vessels appearing in the trial population.
What explains those findings?
The trap also absorbs BMP-9, which is part of what keeps blood vessels stable. People with loss-of-function variants in that pathway develop the same vascular picture.
What did the published trial report?
Trends toward higher lean mass and bone mineral density and lower fat mass, none of which reached statistical significance, alongside the vascular findings.
Why does the expression system matter?
A protein made in mammalian cells and one made in a bacterial system have different glycosylation, and Fc function and half life both depend on it. They are different articles.
What purity method applies?
Size exclusion chromatography rather than reverse phase alone. Aggregation is the failure mode that matters on a dimeric protein and reverse phase will not show it.
What is the handling rule that matters most?
Never agitate it. A dimeric protein driven to an air-liquid interface unfolds and aggregates, and nothing about the solution looks different afterwards.
Compliance Statement
ACE-031 is sold exclusively for laboratory research use. It is not a drug, food, or cosmetic product, and it is not a dietary product of any kind. It is not approved by the FDA or any comparable authority for human or veterinary use, it is a fusion protein rather than a peptide and the handling conventions used elsewhere in this catalogue do not apply to it, its clinical development was discontinued in 2013 after vascular findings appeared in trial participants and the proposed explanation is that the construct absorbs ligands beyond its intended target, it binds several members of a growth factor family so no observed effect can be attributed to the removal of one of them, and no compound in this range is offered for any human or veterinary purpose. This product is not intended to diagnose, treat, cure, or prevent any disease. It must not be given to humans or animals. Purchase is restricted to qualified researchers and institutions operating within applicable laws. All handling is the responsibility of the purchasing laboratory.
19 reviews for ACE-031 1MG