title: Assessment of potential cross-reactivity of human endogenous matrix metalloproteinases with collagenase Clostridium histolyticum antibodies in human sera obtained from patients with Dupuytren's contracture.
abstract: Collagenase Clostridium histolyticum (CCH) contains a fixed ratio of class I (AUX-I) and class II (AUX-II) collagenases and is used as treatment for Dupuytren's contracture. These two Zn-dependent enzymes, produced by the Gram-positive bacterium Clostridium histolyticum, are related functionally to matrix metalloproteinases (MMPs) which, among other functions, degrade the extracellular matrix. Since AUX-I and AUX-II exhibit sequence similarities to human MMPs, we assessed MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin 1), MMP-8 (collagenase 2), and MMP-13 (collagenase 3) for cross-reactivity with anti-AUX-I and anti-AUX-II antibodies in patient serum. Serum samples from 71 subjects enrolled in a long-term clinical study (58 males and 13 females; 63 ± 10 years old [mean ± standard error]) were evaluated for cross-reactivity with the five MMPs using the two validated enzyme-linked immunosorbent assays (ELISAs). Inhibition cutoff points for anti-AUX-I and anti-AUX-II antibodies were based on assay inhibition obtained with a nonspecific protein, bovine gamma globulin, which was tested for each clinical sample. No MMP cross-reactivity was found for any of the 71 clinical antibody-positive sera evaluated. Sequence identity assessments indicated minimal, nonmeaningful alignments of the MMPs and AUX-I/AUX-II. Furthermore, clinical adverse event assessments indicated no safety signals related to MMP inhibition. The bioanalytical results, sequence identity, and clinical assessments consistently did not demonstrate cross-reactivity between CCH antidrug antibodies and endogenous human matrix metalloproteinases. The results presented here suggest that treatment of Dupuytren's contracture patients with CCH does not lead to any clinical adverse events associated with MMP inhibition.
authors.affiliation: Edkins Pharma Services, LLC, Wayne, Pennsylvania, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Edkins
authors.forename: Roland
authors.initials: R
authors.lastname: Koller-Eichhorn
authors.forename: Jack A
authors.initials: JA
authors.lastname: Alhadeff
authors.forename: Ulrich
authors.initials: U
authors.lastname: Mayer
authors.forename: Heinrich
authors.initials: H
authors.lastname: Faust
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Del Tito
mesh_terms: D000368:Aged; D000907:Antibodies, Bacterial / Q000097:blood*; D003429:Cross Reactions; D004387:Dupuytren Contracture / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000276:immunology*; D003012:Microbial Collagenase / Q000276:immunology*; D008875:Middle Aged; D017386:Sequence Homology, Amino Acid
chemical_list: D000907:Antibodies, Bacterial; D020782:Matrix Metalloproteinases; D003012:Microbial Collagenase