Modulation of Macropinocytosis-Mediated Internalization Decreases Ocular Toxicity of Antibody-Drug Conjugates

被引：86

作者：

Zhao, Hui ^{[1
]}

Atkinson, John ^{[1
]}

Gulesserian, Sara ^{[1
]}

Zeng, Zhilan ^{[1
]}

Nater, Jenny ^{[1
]}

Ou, Jimmy ^{[1
]}

Yang, Peng ^{[1
]}

Morrison, Karen ^{[1
]}

Coleman, Jeffrey ^{[1
]}

Malik, Faisal ^{[1
]}

Challita-Eid, Pia ^{[1
]}

Karki, Sher ^{[1
]}

Avina, Hector ^{[1
]}

Hubert, Rene ^{[1
]}

Capo, Linnette ^{[1
]}

Snyder, Josh ^{[1
]}

Moon, Sung-Ju ^{[1
]}

Luethy, Roland ^{[1
]}

Mendelsohn, Brian A. ^{[1
]}

Stover, David R. ^{[1
]}

Donate, Fernando ^{[1
]}

机构：

[1] Agensys Inc, Santa Monica, CA USA

来源：

CANCER RESEARCH | 2018年 / 78卷 / 08期

关键词：

RENAL-CELL CARCINOMA; NON-HODGKIN-LYMPHOMA; TRASTUZUMAB EMTANSINE; DOSE-ESCALATION; BREAST-CANCER; ADC; INHIBITION; CHALLENGES; DISCOVERY; RECEPTOR;

D O I：

10.1158/0008-5472.CAN-17-3202

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

AGS-16C3F is an antibody-drug conjugate (ADC) against ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) containing the mcMMAF linker-payload currently in development for treatment of metastatic renal cell carcinoma. AGS-16C3F and other ADCs have been reported to cause ocular toxicity in patients by unknown mechanisms. To investigate this toxicity, we developed an in vitro assay using human corneal epithelial cells (HCEC) and show that HCECs internalized AGS-16C3F and other ADCs by macropinocytosis, causing inhibition of cell proliferation. We observed the same mechanism for target-independent internalization of AGS-16C3F in fibroblasts andhuman umbilical vein endothelial cells (HUVEC). Macropinocytosis-mediated intake of macromolecules is facilitated by the presence of positive charges or hydrophobic residues on the surface of the macromolecule. Modification of AGS-16C3F, either by attachment of polyglutamate peptides, mutation of residue K16 to D on AGS-16C3F [AGS-16C3F(K16D)], or decreasing the overall hydrophobicity via attachment of polyethylene glycol moieties, significantly reduced cytotoxicity against HCECs and other primary cells. Rabbits treated with AGS-16C3F showed significant ocular toxicity, whereas those treated with AGS-16C3F(K16D) presented with less severe and delayed toxicities. Both molecules displayed similar antitumor activity in a mouse xenograft model. These findings establish a mechanism of action for target-independent toxicities of AGS-16C3F and ADCs in general, and provide methods to ameliorate these toxicities. Significance: These findings reveal a mechanism for nonreceptor-mediated toxicities of antibody drug conjugates and potential solutions to alleviate these toxicities. (C) 2018 AACR.

引用

页码：2115 / 2126

页数：12

共 32 条

[1] Strategies and challenges for the next generation of antibody drug conjugates [J].

Beck, Alain ;

Goetsch, Liliane ;

Dumontet, Charles ;

Corvaia, Nathalie .

NATURE REVIEWS DRUG DISCOVERY, 2017, 16 (05) :315-337

[2] A phase 1 study of weekly dosing of trastuzumab emtansine (T-DM1) in patients with advanced human epidermal growth factor 2-positive breast cancer [J].

Beeram, Muralidhar ;

Krop, Ian E. ;

Burris, Howard A. ;

Girish, Sandhya R. ;

Yu, Wei ;

Lu, Michael W. ;

Holden, Scott N. ;

Modi, Shanu .

CANCER, 2012, 118 (23) :5733-5740

[3] Discovery and Optimization of HKT288, a Cadherin-6-Targeting ADC for the Treatment of Ovarian and Renal Cancers [J].

Bialucha, Carl U. ;

Collins, Scott D. ;

Li, Xiao ;

Saxena, Parmita ;

Zhang, Xiamei ;

Durr, Clemens ;

Lafont, Bruno ;

Prieur, Pierric ;

Shim, Yeonju ;

Mosher, Rebecca ;

Ostrom, David Lee Lance ;

Hu, Tiancen ;

Bilic, Sanela ;

Rajlic, Ivana Liric ;

Capka, Vladimir ;

Jiang, Wei ;

Wagner, Joel P. ;

Elliott, GiNell ;

Veloso, Artur ;

Piel, Jessica C. ;

Flaherty, Meghan M. ;

Mansfield, Keith G. ;

Meseck, Emily K. ;

Rubic-Schneider, Tina ;

London, Anne Serdakowski ;

Tschantz, William R. ;

Kurz, Markus ;

Duc Nguyen ;

Bourret, Aaron ;

Meyer, Matthew J. ;

Faris, Jason E. ;

Janatpour, Mary J. ;

Chan, Vivien W. ;

Yoder, Nicholas C. ;

Catcott, Kalli C. ;

McShea, Molly A. ;

Sun, Xiuxia ;

Gao, Hui ;

Williams, Juliet ;

Hofmann, Francesco ;

Engelman, Jeffrey A. ;

Ettenberg, Seth A. ;

Sellers, William R. ;

Lees, Emma .

CANCER DISCOVERY, 2017, 7 (09) :1030-1045

[4] Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models [J].

Challita-Eid, Pia M. ;

Satpayev, Daulet ;

Yang, Peng ;

An, Zili ;

Morrison, Karen ;

Shostak, Yuriy ;

Raitano, Arthur ;

Nadell, Rossana ;

Liu, Wendy ;

Lortie, Dawn Ratay ;

Capo, Linnette ;

Verlinsky, Alla ;

Leavitt, Monica ;

Malik, Faisal ;

Avina, Hector ;

Guevara, Claudia I. ;

Dinh, Nick ;

Karki, Sher ;

Anand, Banmeet S. ;

Pereira, Daniel S. ;

Joseph, Ingrid B. J. ;

Donate, Fernando ;

Morrison, Kendall ;

Stover, David R. .

CANCER RESEARCH, 2016, 76 (10) :3003-3013

[5] Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells [J].

Commisso, Cosimo ;

Davidson, Shawn M. ;

Soydaner-Azeloglu, Rengin G. ;

Parker, Seth J. ;

Kamphorst, Jurre J. ;

Hackett, Sean ;

Grabocka, Elda ;

Nofal, Michel ;

Drebin, Jeffrey A. ;

Thompson, Craig B. ;

Rabinowitz, Joshua D. ;

Metallo, Christian M. ;

Vander Heiden, Matthew G. ;

Bar-Sagi, Dafna .

NATURE, 2013, 497 (7451) :633-+

[6] A phase 1 clinical trial of ASG-5ME, a novel drug-antibody conjugate targeting SLC44A4, in patients with advanced pancreatic and gastric cancers [J].

Coveler, Andrew L. ;

Ko, Andrew H. ;

Catenacci, Daniel V. T. ;

Von Hoff, Daniel ;

Becerra, Carlos ;

Whiting, Nancy C. ;

Yang, Jing ;

Wolpin, Brian .

INVESTIGATIONAL NEW DRUGS, 2016, 34 (03) :319-328

[7] New developments for antibody-drug conjugate-based therapeutic approaches [J].

de Goeij, Bart E. C. G. ;

Lambert, John M. .

CURRENT OPINION IN IMMUNOLOGY, 2016, 40 :14-23

[8] Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates [J].

Donaghy, Heather .

MABS, 2016, 8 (04) :659-671

[9] AGS16F Is a Novel Antibody Drug Conjugate Directed against ENPP3 for the Treatment of Renal Cell Carcinoma [J].

Donate, Fernando ;

Raitano, Arthur ;

Morrison, Kendall ;

An, Zili ;

Capo, Linnette ;

Avina, Hector ;

Karki, Sher ;

Morrison, Karen ;

Yang, Peng ;

Ou, Jimmy ;

Moriya, Ryuichi ;

Shostak, Yuriy ;

Malik, Faisal ;

Nadell, Rossana ;

Liu, Wendy ;

Satpayev, Daulet ;

Atkinson, John ;

Joseph, Ingrid B. J. ;

Pereira, Daniel S. ;

Challita-Eid, Pia M. ;

Stover, David R. .

CLINICAL CANCER RESEARCH, 2016, 22 (08) :1989-1999

[10] Ocular Adverse Events Associated with Antibody-Drug Conjugates in Human Clinical Trials [J].

Eaton, Joshua Seth ;

Miller, Paul E. ;

Mannis, Mark J. ;

Murphy, Christopher J. .

JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS, 2015, 31 (10) :589-604

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