Preclinical validation of anti-TMEFF2-auristatin E-conjugated antibodies in the treatment of prostate cancer.
Current treatments for advanced stage, hormone-resistant prostate cancer are largely ineffective, leading to high patient mortality and morbidity. To fulfill this unmet medical need, we used global gene expression profiling to identify new potential antibody-drug conjugate (ADC) targets that showed maximal prostate cancer-specific expression. TMEFF2, a gene encoding a plasma membrane protein with two follistatin-like domains and one epidermal growth factor-like domain, had limited normal tissue distribution and was highly overexpressed in prostate cancer. Immunohistochemistry analysis using a specific monoclonal antibody (mAb) to human TMEFF2 showed significant protein expression in 74% of primary prostate cancers and 42% of metastatic lesions from lymph nodes and bone that represented both hormone-naïve and hormone-resistant disease. To evaluate anti-TMEFF2 mAbs as potential ADCs, one mAb was conjugated to the cytotoxic agent auristatin E via a cathepsin B-sensitive valine-citrulline linker. This ADC, Pr1-vcMMAE, was used to treat male severe combined immunodeficient mice bearing xenografted LNCaP and CWR22 prostate cancers expressing TMEFF2. Doses of 3 to 10 mg/kg of this specific ADC resulted in significant and sustained tumor growth inhibition, whereas an isotype control ADC had no significant effect. Similar efficacy and specificity was shown with huPr1-vcMMAE, a humanized anti-TMEFF2 ADC. No overt in vivo toxicity was observed with either murine or human ADC, despite significant cross-reactivity of anti-TMEFF2 mAb with the murine TMEFF2 protein, implying minimal toxicity to other body tissues. These data support the further evaluation and clinical testing of huPr1-vcMMAE as a novel therapeutic for the treatment of metastatic and hormone-resistant prostate cancer.
Afar
Daniel E H
DE
Protein Design Labs, Inc., 34801 Campus Drive, Fremont, CA 94555, USA. dafar@pdl.com
Bhaskar
Vinay
V
Ibsen
Eric
E
Breinberg
Danna
D
Henshall
Susan M
SM
Kench
James G
JG
Drobnjak
Marija
M
Powers
Rick
R
Wong
Melanie
M
Evangelista
Ferdinand
F
O'Hara
Chris
C
Powers
David
D
DuBridge
Robert B
RB
Caras
Ingrid
I
Winter
Ruth
R
Anderson
Terri
T
Solvason
Nanette
N
Stricker
Phillip D
PD
Cordon-Cardo
Carlos
C
Scher
Howard I
HI
Grygiel
John J
JJ
Sutherland
Robert L
RL
Murray
Richard
R
Ramakrishnan
Vanitha
V
Law
Debbie A
DA
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D005434:Flow Cytometry; D038681:Follistatin / Q000737:chemistry; D006801:Humans; D006825:Hybridomas / Q000737:chemistry; D007150:Immunohistochemistry; D007700:Kinetics; D008207:Lymphatic Metastasis; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry* / Q000276:immunology*; D051379:Mice; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D009842:Oligopeptides / Q000737:chemistry / Q000627:therapeutic use*; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D020349:Surface Plasmon Resonance; D013997:Time Factors; D014162:Transfection
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018076:DNA, Complementary; D038681:Follistatin; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009842:Oligopeptides; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C423567:TMEFF2 protein, human; C105791:soblidotin