Trevogrumab: Molecular Structure
Chemical properties, amino acid sequence, and structural analysis
📌TL;DR
- •Molecular formula: Complex immunoglobulin
- •Molecular weight: 150000 Da
- •Half-life: Specific half-life not publicly reported. As an IgG4 antibody, the expected half-life is approximately 21 days, consistent with typical IgG4 pharmacokinetics and FcRn-mediated recycling.
Amino Acid Sequence
221 amino acids
Formula
Complex immunoglobulin
Molecular Weight
150000 Da
Half-Life
Specific half-life not publicly reported. As an IgG4 antibody, the expected half-life is approximately 21 days, consistent with typical IgG4 pharmacokinetics and FcRn-mediated recycling.
Molecular Structure#
Trevogrumab is a fully human monoclonal antibody of the IgG4-kappa subclass, with an approximate molecular weight of 150 kDa. Like all IgG antibodies, it consists of:
- 2 heavy chains: Gamma-4 isotype (~50 kDa each)
- 2 light chains: Kappa type (~25 kDa each)
- Disulfide bonds: Inter-chain and intra-chain disulfide bridges maintaining quaternary structure
- Glycosylation: N-linked glycosylation at Asn297 in the Fc region (typical for IgG antibodies)
IgG4 Subclass Properties#
The choice of IgG4 isotype is significant for trevogrumab's function:
| Property | IgG4 Characteristic | Relevance to Trevogrumab |
|---|---|---|
| Effector function | Minimal ADCC and CDC | Avoids immune-mediated cell killing |
| Complement activation | Very low | Reduces inflammatory side effects |
| FcRn binding | Normal | Maintains long serum half-life |
| Fab-arm exchange | Possible in vivo | S228P mutation typically introduced to prevent |
| Half-life | ~21 days | Supports Q2W or Q4W dosing intervals |
IgG4 is preferred over IgG1 for neutralizing antibodies like trevogrumab because its minimal effector function reduces the risk of unwanted immune activation while still providing high-affinity target engagement.
Target Binding Properties#
Myostatin Selectivity#
Trevogrumab was generated using Regeneron's VelocImmune technology, which produces fully human antibodies from genetically engineered mice. A critical feature of REGN1033 is its selectivity:
| Ligand | Binding by Trevogrumab | Binding by ActRIIB-Fc (e.g., ACE-031) |
|---|---|---|
| Myostatin (GDF-8) | High affinity | Yes |
| GDF-11 | No cross-reactivity | Yes |
| Activin A | No binding | Yes |
| BMP-9/10 | No binding | Yes |
This selectivity profile distinguishes trevogrumab from receptor-level inhibitors like bimagrumab (anti-ActRII antibody) or ACE-031 (ActRIIB-Fc fusion), which block multiple TGF-beta superfamily ligands.
Myostatin Forms Recognized#
REGN1033 binds all three physiological forms of myostatin:
- Mature myostatin dimer: The active signaling form (~25 kDa homodimer)
- Latent myostatin complex: Mature myostatin bound to its propeptide, preventing receptor interaction
- Myostatin precursor (proform): The unprocessed full-length protein before furin cleavage
This comprehensive binding profile ensures neutralization of myostatin regardless of its processing state.
Pharmacokinetics#
| Parameter | Value | Notes |
|---|---|---|
| Molecular weight | ~150 kDa | Full IgG4 antibody |
| Expected half-life | ~21 days | Consistent with IgG4 class |
| Administration | Subcutaneous injection | Self-administration possible |
| Absorption | Slow, from SC depot | Typical for SC antibody dosing |
| Metabolism | Lysosomal degradation | FcRn-mediated recycling extends half-life |
| Elimination | Catabolism + target-mediated | Target-mediated disposition at low doses |
Comparison with Other Anti-Myostatin Approaches#
| Molecule | Type | MW | Target | Selectivity |
|---|---|---|---|---|
| Trevogrumab (REGN1033) | Human IgG4 mAb | ~150 kDa | Myostatin directly | Highly selective |
| Bimagrumab (BYM338) | Human IgG1 mAb | ~145 kDa | ActRIIA/ActRIIB | Broad (multiple ligands) |
| Apitegromab (SRK-015) | Humanized IgG4 mAb | ~150 kDa | Latent myostatin | Selective (latent form only) |
| ACE-031 (ramatercept) | ActRIIB-Fc fusion | ~90 kDa | ActRIIB ligand trap | Broad (discontinued) |
| Domagrozumab (PF-06252616) | Humanized IgG1 mAb | ~150 kDa | Myostatin | Selective |
Production and Manufacturing#
As a fully human monoclonal antibody, trevogrumab is produced in mammalian cell culture (likely CHO cells) using recombinant DNA technology. The manufacturing process involves:
- Cell line development and banking
- Large-scale bioreactor cultivation
- Protein A chromatography purification
- Formulation for subcutaneous delivery
- Sterile fill-finish under GMP conditions
This complex manufacturing distinguishes antibody therapeutics from synthetic peptides, which can be produced by chemical synthesis. Trevogrumab cannot be synthesized by peptide synthesis methods.
Related Reading#
Frequently Asked Questions About Trevogrumab
What type of peptide is Trevogrumab?
Trevogrumab (REGN1033) is a fully human IgG4 monoclonal antibody that selectively binds and neutralizes myostatin (GDF-8), the primary negative regulator of skeletal muscle mass. Developed by Regeneron Pharmaceuticals, it is being evaluated in the Phase 2 COURAGE trial in combination with semaglutide for preserving lean mass during weight loss in patients with obesity. At 26 weeks, adding trevogrumab to semaglutide preserved approximately 50% of lean mass that would otherwise be lost, while also increasing fat mass loss compared to semaglutide alone.
What is the half-life of Trevogrumab?
The reported half-life of Trevogrumab is Specific half-life not publicly reported. As an IgG4 antibody, the expected half-life is approximately 21 days, consistent with typical IgG4 pharmacokinetics and FcRn-mediated recycling.. Half-life can vary depending on the route of administration, formulation, and individual factors. This information is based on available preclinical or pharmacokinetic data.
What is the amino acid sequence of Trevogrumab?
The amino acid sequence of Trevogrumab is Full amino acid sequence not publicly disclosed. Trevogrumab is a fully human IgG4-kappa monoclonal antibody consisting of two heavy chains (gamma-4 isotype) and two light chains (kappa type) connected by disulfide bonds.. Trevogrumab is a fully human IgG4-kappa monoclonal antibody (~150 kDa) that selectively binds myostatin (GDF-8) with high affinity. The antibody binds all three forms of myostatin: the mature dimer, the latent complex, and the precursor proform. It shows no cross-reactivity with GDF-11, distinguishing it from broader receptor-level inhibitors.. This sequence determines its biological activity and binding properties.
How stable is Trevogrumab in storage?
Trevogrumab is typically supplied as a lyophilized powder for maximum stability. Trevogrumab is a fully human IgG4-kappa monoclonal antibody (~150 kDa) that selectively binds myostatin (GDF-8) with high affinity. The antibody binds all three forms of myostatin: the mature dimer, the latent complex, and the precursor proform. It shows no cross-reactivity with GDF-11, distinguishing it from broader receptor-level inhibitors.. When reconstituted, it should be stored refrigerated at 2-8 degrees C and protected from light. Lyophilized powder should be stored at -20 degrees C.
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