Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts.
OBJECTIVE
Invasion and metastasis of malignant epithelial cells into normal tissues is accompanied by adaptive changes in the mesenchyme-derived supporting stroma of the target organs. Altered gene expression in these nontransformed stromal cells provides potential targets for therapy. The present study was undertaken to determine the antitumor effects of an antibody-conjugate against fibroblast activation protein-alpha, a cell surface protease of activated tumor fibroblasts.


METHODS
A novel antibody-maytansinoid conjugate, monoclonal antibody (mAb) FAP5-DM1, was developed to target a shared epitope of human, mouse, and cynomolgus monkey fibroblast activation protein-alpha, enabling preclinical efficacy and tolerability assessments. We have used stroma-rich models in immunodeficient mice, which recapitulate the histotypic arrangement found in human epithelial cancers.


RESULTS
Treatment with mAb FAP5-DM1 induced long-lasting inhibition of tumor growth and complete regressions in xenograft models of lung, pancreas, and head and neck cancers with no signs of intolerability. Analysis of chemically distinct conjugates, resistance models, and biomarkers implicates a unique mode of action, with mitotic arrest and apoptosis of malignant epithelial cells coupled to disruption of fibroblastic and vascular structures.


CONCLUSIONS
We show that mAb FAP5-DM1 combines excellent efficacy and tolerability and provides a first assessment of the mode of action of a novel drug candidate for tumor stroma targeting, thus encouraging further development toward clinical testing of this treatment paradigm.
Ostermann
Elinborg
E
Boehringer Ingelheim Austria GmbH, Austria.
Garin-Chesa
Pilar
P
Heider
Karl Heinz
KH
Kalat
Milena
M
Lamche
Herbert
H
Puri
Christina
C
Kerjaschki
Dontscho
D
Rettig
Wolfgang J
WJ
Adolf
Guenther R
GR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D000918:Antibody Specificity; D000951:Antigens, Neoplasm / Q000276:immunology*; D014408:Biomarkers, Tumor / Q000276:immunology*; D010450:Endopeptidases; D005347:Fibroblasts / Q000276:immunology*; D018093:Gelatinases; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D008252:Macaca fascicularis; D008453:Maytansine / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use; D008565:Membrane Proteins; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D012697:Serine Endopeptidases / Q000276:immunology*; D020349:Surface Plasmon Resonance; D000099167:Fibroblast Activation Protein Alpha
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D010450:Endopeptidases; D018093:Gelatinases; D018796:Immunoconjugates; D008453:Maytansine; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha