AGS16F Is a Novel Antibody Drug Conjugate Directed against ENPP3 for the Treatment of Renal Cell Carcinoma

被引：36

作者：

Donate, Fernando ^{[1
]}

Raitano, Arthur ^{[1
]}

Morrison, Kendall ^{[1
]}

An, Zili ^{[1
]}

Capo, Linnette ^{[1
]}

Avina, Hector ^{[1
]}

Karki, Sher ^{[1
]}

Morrison, Karen ^{[1
]}

Yang, Peng ^{[1
]}

Ou, Jimmy ^{[1
]}

Moriya, Ryuichi ^{[1
,2
]}

Shostak, Yuriy ^{[1
]}

Malik, Faisal ^{[1
]}

Nadell, Rossana ^{[1
]}

Liu, Wendy ^{[1
]}

Satpayev, Daulet ^{[1
,3
]}

Atkinson, John ^{[1
]}

Joseph, Ingrid B. J. ^{[1
]}

Pereira, Daniel S. ^{[1
]}

Challita-Eid, Pia M. ^{[1
]}

Stover, David R. ^{[1
]}

机构：

[1] Agensys Inc, 1800 Stewart St, Santa Monica, CA 90404 USA

[2] Astellas Pharma Inc, Drug Discovery Res, Tsukuba, Ibaraki, Japan

[3] ImaginAb, Inglewood, CA USA

来源：

CLINICAL CANCER RESEARCH | 2016年 / 22卷 / 08期

关键词：

CANCER-THERAPY; MAST-CELLS; SURFACE ANTIGENS; HUMAN BASOPHILS; LOCALIZATION; EXPRESSION; E-NPP3/CD203C/PD-I-BETA/B10/GP130(RB13-6); LYMPHOMA; CLONING; 97A6;

D O I：

10.1158/1078-0432.CCR-15-1542

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: New cancer-specific antigens are required for the design of novel antibody-drug conjugates (ADC) that deliver tumor-specific and highly potent cytotoxic therapy. Experimental Design: Suppression subtractive hybridization identified ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3 or CD203c) as a potential human cancer-specific antigen. Antibodies targeting the extracellular domain of human ENPP3 were produced and selected for specific binding to ENPP3. Expression of ENPP3 in normal and cancer tissue specimens was evaluated by immunohistochemistry (IHC). ADCs comprising anti-ENPP3 Ab conjugated with maleimidocaproyl monomethyl auristatin F via a noncleavable linker (mcMMAF) were selected for therapeutic potential using binding and internalization assays, cytotoxicity assays, and tumor growth inhibition in mouse xenograft models. Pharmacodynamic markers were evaluated by IHC in tissues and ELISA in blood. Results: ENPP3 was highly expressed in clear cell renal cell carcinoma: 92.3% of samples were positive and 83.9% showed high expression. By contrast, expression was negligible in normal tissues examined, with the exception of the kidney. High expression was less frequent in papillary renal cell carcinoma and hepatocellular carcinoma samples. AGS16F, an anti-ENPP3 antibody-mcMMAF conjugate, inhibited tumor growth in three different renal cell carcinoma (RCC) xenograft models. AGS16F localized to tumors, formed the active metabolite Cys-mcMMAF, induced cell-cycle arrest and apoptosis, and increased blood levels of caspase-cleaved cytokeratin-18, a marker of epithelial cell death. Conclusions: AGS16F is a promising new therapeutic option for patients with RCC and is currently being evaluated in a phase I clinical trial. (C) 2015 AACR.

引用

页码：1989 / 1999

页数：11

共 36 条

[1] Antibody-drug conjugates Present and future [J].

Beck, Alain ;

Reichert, Janice M. .

MABS, 2014, 6 (01) :15-17

[2] The basophil activation marker defined by antibody 97A6 is identical to the ectonucleotide pyrophosphatase/phosphodiesterase 3 [J].

Bühring, HJ ;

Seiffert, M ;

Giesert, C ;

Marxer, A ;

Kanz, L ;

Valent, P ;

Sano, K .

BLOOD, 2001, 97 (10) :3303-3305

[3]

Bühring HJ, 1999, BLOOD, V94, P2343

[4] AFFINITY PURIFICATION AND CDNA CLONING OF RAT NEURAL DIFFERENTIATION AND TUMOR-CELL SURFACE-ANTIGEN GP130(RB13-6) REVEALS RELATIONSHIP TO HUMAN AND MURINE PC-1 [J].

DEISSLER, H ;

LOTTSPEICH, F ;

RAJEWSKY, MF .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (17) :9849-9855

[5] Enhanced activity of monomethylauristatin F through monoclonal antibody delivery: Effects of linker technology on efficacy and toxicity [J].

Doronina, SO ;

Mendelsohn, BA ;

Bovee, TD ;

Cerveny, CG ;

Alley, SC ;

Meyer, DL ;

Oflazoglu, E ;

Toki, BE ;

Sanderson, RJ ;

Zabinski, RF ;

Wahl, AF ;

Senter, PD .

BIOCONJUGATE CHEMISTRY, 2006, 17 (01) :114-124

[6] Development of potent monoclonal antibody auristatin conjugates for cancer therapy [J].

Doronina, SO ;

Toki, BE ;

Torgov, MY ;

Mendelsohn, BA ;

Cerveny, CG ;

Chace, DF ;

DeBlanc, RL ;

Gearing, RP ;

Bovee, TD ;

Siegall, CB ;

Francisco, JA ;

Wahl, AF ;

Meyer, DL ;

Senter, PD .

NATURE BIOTECHNOLOGY, 2003, 21 (07) :778-784

[7] Physiological and pathophysiological functions of the ecto-nucleotide pyrophosphatase/phosphodiesterase family [J].

Goding, JW ;

Grobben, B ;

Slegers, H .

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, 2003, 1638 (01) :1-19

[8] Antibody engineering via genetic engineering of the mouse: XenoMouse strains are a vehicle for the facile generation of therapeutic human monoclonal antibodies [J].

Green, LL .

JOURNAL OF IMMUNOLOGICAL METHODS, 1999, 231 (1-2) :11-23

[9] A novel high-through-put assay for screening of pro-apoptotic drugs [J].

Hägg, M ;

Bivén, K ;

Ueno, T ;

Rydlander, L ;

Björklund, P ;

Wiman, KG ;

Shoshan, M ;

Linder, S .

INVESTIGATIONAL NEW DRUGS, 2002, 20 (03) :253-259

[10] Antibody-drug conjugates for cancer therapy: The technological and regulatory challenges of developing drug-biologic hybrids [J].

Hamilton, Gregory S. .

BIOLOGICALS, 2015, 43 (05) :318-332

← 1 2 3 4 →