IGF1-LR3

IGF-1 LR3 (also written IGF1 LR3, Long R3 IGF-I or LR3IGF-I) is a recombinant analog of human insulin-like growth factor I, built in Escherichia coli as a fusion peptide: the IGF-I sequence carries a 13-residue N-terminal extension, the first 11 amino acids of methionyl porcine growth hormone plus the dipeptide Val-Asn, and arginine replaces glutamate at position 3.

The authors named the family Long IGF-I, Long [Gly3]-IGF-I and Long [Arg3]-IGF-I by the IGF-I sequence present, so LR3 means the long extension plus the Arg3 substitution (King et al., 1992; Francis et al., 1992). The literature is rodent, livestock and cell-culture work, much of it from one Australian group in the 1990s, plus later analytical chemistry.

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Published work on Long R3 IGF-I falls into six areas. Each summary below states the model used.

Construction and design rationale

Two 1992 papers describe the expression system. In the first, a fusion protein carrying a 46-residue porcine growth hormone leader was isolated from inclusion bodies, cleaved at an Asn-Gly bond to release native-length IGF-I, [Gly3]-IGF-I and [Arg3]-IGF-I, refolded and purified, with purity established by HPLC and N-terminal sequence analysis; the Long analogs of the second paper keep a shorter 11-residue leader plus Val-Asn.

In L6 rat myoblasts, [Gly3]-IGF-I and [Arg3]-IGF-I were more potent than IGF-I at stimulating protein and DNA synthesis and at inhibiting protein breakdown, yet both bound slightly less well to the type 1 receptor, which the authors attributed to weaker binding-protein association rather than stronger receptor binding (King et al., 1992). The hydrophobic extension also raised folding yields, and in chicken embryo fibroblasts, a line that secretes no detectable binding proteins, Long [Arg3]-IGF-I was less potent than IGF-I (Francis et al., 1992).

Binding protein affinity

IGF-I has roughly 1000-fold higher affinity than LR3IGF-I for IGFBP-3, IGFBP-4, total rat plasma binding proteins and L6 myoblast binding protein, which tracked with a 5 to 10-fold greater potency for the analog in L6 myoblast culture (Ballard et al., 1993). A five-species survey found binding differed markedly between rat, sheep, human, pig and chicken plasma, so one species does not predict another (Lord et al., 1994).

Clearance and distribution in rodents

In pregnant and virgin rats given labeled tracer, the metabolic clearance rate was 9.19 and 9.84 milliliters per minute per kilogram for LR3IGF-I against 2.88 and 0.90 for IGF-I, so pregnancy, when plasma binding proteins fall, sped clearance of IGF-I but not of the analog. Most analog tracer was free peptide rather than bound in the 150 kDa complex, and tissue distribution differed between the two (Bastian et al., 1993).

Rodent growth and gut models

In rats made catabolic with dexamethasone, the analog was about 2.5-fold more potent than IGF-I at restoring body weight and nitrogen retention over 7 days, with coordinate changes in muscle protein turnover markers and gut weight increases of up to 45 percent (Tomas et al., 1992).

In normal female rats treated for 14 days through osmotic minipumps, gut weight, small intestinal weight and intestinal length rose with concentration, with more crypt cells and cells per villus column while the crypt growth fraction stayed unchanged (Steeb et al., 1994). A separate 14-day rat study put the analog about 6-fold above IGF-I on growth measures (Ballard et al., 1993).

Species where results reversed

In finisher pigs, a four-day infusion decreased average daily gain, food intake and plasma IGFBP-3, IGF-I and insulin, and lowered mean plasma growth hormone by 23 percent, so the analog inhibited rather than stimulated growth in that species (Dunaiski et al., 1997).

In pigs and marmoset monkeys, variants that bind binding proteins poorly were 2 to 3-fold more potent than IGF-I at lowering plasma glucose and kept it lower for longer, with LR3IGF-I itself tested in pigs (Tomas et al., 1997). In growth-restricted fetal sheep, one week of treatment did not raise fetal weight and circulating amino acids fell (White et al., 2025).

Cell-culture use and analytical detection

The analog is widely used as a serum-free culture supplement. In two recombinant protein-expressing Chinese hamster ovary lines it sustained viability under production conditions better than insulin (Morris and Schmid, 2000), and in HEK293 cells it was a more potent growth and survival factor than insulin or native IGF-I, supporting CHO cells at concentrations at least 200-fold below those needed for insulin (Voorhamme and Yandell, 2006).

On the analytical side, an immunopurification and high-resolution mass spectrometry method detected LongR3-IGF-I and related analogs in serum, identified a new N-terminal degradation product, Des(1)-LongR3-IGF-I, alongside two known ones, and reported abundant oxidized forms in unregulated market products (Mongongu et al., 2021). An earlier case report identified His-tagged Long-R3-IGF-I, a form normally made for biochemical studies, in an injection vial from a black-market product (Kohler et al., 2010).