CJC-1295 Drug Affinity Complex

CJC-1295 with DAC is a synthetic analog of growth hormone-releasing hormone (GHRH), the hypothalamic peptide that signals the pituitary to release growth hormone (GH). It keeps the first 29 residues of human GHRH with four stabilizing substitutions and adds a C-terminal lysine carrying a reactive maleimide group, the drug affinity complex (DAC), which bonds to serum albumin.

ConjuChem scientists in Montreal picked it as the best of three maleimido derivatives tested in rats, where it persisted in plasma beyond 72 hours (Jetté et al., 2005).

The evidence base is small: one rat paper describing the compound, three reports from healthy-adult studies, two mouse studies and a few drug-testing methods papers. Each area below states its model.

What the DAC modification does

The drug affinity complex is a lysine added at the C-terminus and linked through its side chain to 3-maleimidopropionic acid (MPA). The maleimide reacts with the free thiol on cysteine 34 of serum albumin, so the peptide travels attached to albumin. In the original study, albumin conjugates resisted dipeptidyl peptidase IV and stayed active on rat pituitary cells, and in rats a CJC-1295 band at the albumin position appeared by 15 minutes and persisted beyond 24 hours (Jetté et al., 2005).

Albumin is long-lived partly because the IgG receptor FcRn also binds and shields it; its lifespan was shortened in FcRn-deficient mice (Chaudhury et al., 2003). Once bound, CJC-1295 behaves as a macromolecular protein with no defined molecular weight (Timms et al., 2019). CJC-1295 No DAC, also sold as Mod GRF 1-29, lacks the lysine and maleimide, so it cannot bond to albumin. Models: cell culture, rats, mice and equine plasma.

How a GHRH analog acts

GHRH acts through its own G protein-coupled receptor. Expressed in a human kidney cell line, the cloned human receptor bound GHRH with high affinity, and GHRH raised cyclic AMP in those cells; in rats, its mRNA was found predominantly in the anterior pituitary (Mayo, 1992).

Native GHRH is short-lived: plasma clips two residues from its amino terminus, leaving a fragment with under one thousandth of the activity, and in normal subjects intact GHRH disappeared with a half-life of 6.8 minutes (Frohman et al., 1986). CJC-1295 carries D-alanine at that cleavage site. Models: transfected cells, human plasma and healthy volunteers.

Studies in healthy adults

Two randomized, placebo-controlled, double-blind trials of 28 and 49 days enrolled healthy adults aged 21 to 61. After one injection, mean GH rose two to ten fold for six days or more and IGF-1 rose 1.5 to three fold for 9 to 11 days, scaling with the amount given. The estimated half-life was 5.8 to 8.1 days, IGF-1 stayed above baseline up to 28 days after repeated exposure, and no serious adverse reactions were reported (Teichman et al., 2006).

In healthy men sampled every 20 minutes overnight, one week after CJC-1295, GH pulse frequency and size were unchanged while trough GH rose 7.5 fold and IGF-1 45% (Ionescu and Frohman, 2006). Serum proteomics in 11 healthy young men a week after CJC-1295 found protein changes the authors proposed as candidate markers of GH or IGF-1 action (Sackmann-Sala et al., 2009). Model: healthy human adults.

Mouse growth models

GHRH knockout mice make no releasing hormone, and a GHRH analog given twice daily had not normalized their growth. Given 2 micrograms of CJC-1295 every 24, 48 or 72 hours for five weeks from one week of age, they reached normal body weight and length only on the daily schedule, and pituitary GH mRNA rose with signs of somatotroph proliferation (Alba et al., 2006).

In dwarf mice lacking brain M3 muscarinic receptors, daily CJC-1295 for eight weeks restored pituitary size, serum GH and IGF-1 and longitudinal growth, which the authors read as a defect in hypothalamic GHRH neurons rather than the pituitary (Gautam et al., 2009). Model: genetically modified mice.

Development, regulation and detection

ClinicalTrials.gov lists one CJC-1295 study: a 12-week, placebo-controlled phase 2 trial in adults with HIV-associated visceral obesity, sponsored by the developer, ConjuChem (NCT00267527). It is listed as terminated, with a 2006 completion date and no stated reason or posted findings.

Names are also used loosely: a preparation analyzed in Norway in 2009 held a 29-residue amidated peptide matching one marketed as CJC-1295, without the conjugating lysine (Henninge et al., 2010). Sources: trial registry, regulator pages and mass spectrometry of an unknown preparation.