Cathepsin B Nuclear Flux in a DNA-Guided "Antinuclear Missile" Cancer Therapy

被引：4

作者：

Cao, Fei ^{[1
]}

Tang, Caroline ^{[1
]}

Chen, Xiaoyong ^{[1
]}

Tu, Zewei ^{[2
]}

Jin, Ying ^{[3
]}

Turk, Olivia M. ^{[1
]}

Nishimura, Robert N. ^{[4
,5
]}

Ebens, Allen ^{[6
]}

Dubljevic, Valentina ^{[7
]}

Campbell, James A. ^{[7
]}

Zhou, Jiangbing ^{[2
,8
]}

Hansen, James E. ^{[1
,8
]}

机构：

[1] Yale Sch Med, Dept Therapeut Radiol, New Haven, CT 06510 USA

[2] Yale Sch Med, Dept Neurosurg, New Haven, CT 06510 USA

[3] Yale Sch Med, Dept Surg, Div Vasc Surg & Endovasc Therapy, New Haven, CT 06510 USA

[4] Greater Los Angeles Vet Affairs Healthcare Syst, Dept Res & Dev, Los Angeles, CA 90073 USA

[5] UCLA, Dept Neurol, David Geffen Sch Med, Los Angeles, CA 90095 USA

[6] Adanate, Palo Alto, CA 94305 USA

[7] Patrys Ltd, Melbourne 3205, Australia

[8] Yale Canc Ctr, New Haven, CT 06510 USA

来源：

ACS CENTRAL SCIENCE | 2024年 / 10卷 / 08期

关键词：

BRENTUXIMAB VEDOTIN; EXTRACELLULAR DNA; AUTOANTIBODY; ISCHEMIA;

D O I：

10.1021/acscentsci.4c00559

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Some antinuclear antibodies (ANAs) bind extracellular nucleic acids released into tumor environments and are pulled into the nuclei of live cancer cells through nucleoside salvage pathways, independent of tumor-specific surface antigens. Here we show that ANA nuclear penetration induces nuclear flux by the lysosomal protease cathepsin B and leverage this mechanism to design an antinuclear antibody-drug conjugate (ANADC) with cathepsin B-labile drug linker. The ANADC targets nucleic acid exhaust from necrotic tumors and crosses membrane barriers through nucleoside salvage as a DNA-seeking and tumor agnostic "antinuclear missile" cancer therapy.

引用

页码：1562 / 1572

页数：11

共 32 条

[1] Brentuximab vedotin activity in diffuse large B-cell lymphoma with CD30 undetectable by visual assessment of conventional immunohistochemistry [J].

Bartlett, Nancy L. ;

Smith, Mitchell R. ;

Siddiqi, Tanya ;

Advani, Ranjana H. ;

O'Connor, Owen A. ;

Sharman, Jeff P. ;

Feldman, Tatyana ;

Savage, Kerry J. ;

Shustov, Andrei R. ;

Diefenbach, Catherine S. ;

Oki, Yasuhiro ;

Palanca-Wessels, Maria Corinna ;

Uttarwar, Mayur ;

Li, Martha ;

Yang, Jing ;

Jacobsen, Eric D. .

LEUKEMIA & LYMPHOMA, 2017, 58 (07) :1607-1616

[2] Understanding and interpreting antinuclear antibody tests in systemic rheumatic diseases [J].

Bossuyt, Xavier ;

De Langhe, Ellen ;

Borghi, Maria Orietta ;

Meroni, Pier Luigi .

NATURE REVIEWS RHEUMATOLOGY, 2020, 16 (12) :715-726

[3] Cathepsin B Is Dispensable for Cellular Processing of Cathepsin B-Cleavable Antibody-Drug Conjugates [J].

Caculitan, Nina G. ;

Chuh, Josefa dela Cruz ;

Ma, Yong ;

Zhang, Donglu ;

Kozak, Katherine R. ;

Liu, Yichin ;

Pillow, Thomas H. ;

Sadowsky, Jack ;

Cheung, Tommy K. ;

Phung, Qui ;

Haley, Benjamin ;

Lee, Byoung-Chul ;

Akita, Robert W. ;

Sliwkowski, Mark X. ;

Polson, Andrew G. .

CANCER RESEARCH, 2017, 77 (24) :7027-7037

[4] A lupus anti-DNA autoantibody mediates autocatalytic, targeted delivery of nanoparticles to tumors [J].

Chen, Zeming ;

Patel, Jaymin M. ;

Noble, Philip W. ;

Garcia, Cesar ;

Hong, Zhangyong ;

Hansen, James E. ;

Zhou, Jiangbing .

ONCOTARGET, 2016, 7 (37) :59965-59975

[5] Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer [J].

Cortes, J. ;

Kim, S. -B ;

Chung, W. -P ;

Im, S. -A ;

Park, Y. H. ;

Hegg, R. ;

Kim, M. H. ;

Tseng, L. -M ;

Petry, V ;

Chung, C. -F ;

Iwata, H. ;

Hamilton, E. ;

Curigliano, G. ;

Xu, B. ;

Huang, C. -S ;

Kim, J. H. ;

Chiu, J. W. Y. ;

Pedrini, J. L. ;

Lee, C. ;

Liu, Y. ;

Cathcart, J. ;

Bako, E. ;

Verma, S. ;

Hurvitz, S. A. .

NEW ENGLAND JOURNAL OF MEDICINE, 2022, 386 (12) :1143-1154

[6] Cathepsin B-labile dipeptide linkers for lysosomal release of doxorubicin from internalizing immunoconjugates: Model studies of enzymatic drug release and antigen-specific in vitro anticancer activity [J].

Dubowchik, GM ;

Firestone, RA ;

Padilla, L ;

Willner, D ;

Hofstead, SJ ;

Mosure, K ;

Knipe, JO ;

Lasch, SJ ;

Trail, PA .

BIOCONJUGATE CHEMISTRY, 2002, 13 (04) :855-869

[7] Bevacizumab (Avastin®) in cancer treatment: A review of 15 years of clinical experience and future outlook [J].

Garcia, Josep ;

Hurwitz, Herbert, I ;

Sandler, Alan B. ;

Miles, David ;

Coleman, Robert L. ;

Deurloo, Regula ;

Chinot, Olivier L. .

CANCER TREATMENT REVIEWS, 2020, 86

[8] Impact of Endocytosis Mechanisms for the Receptors Targeted by the Currently Approved Antibody-Drug Conjugates (ADCs)-A Necessity for Future ADC Research and Development [J].

Hammood, Manar ;

Craig, Andrew W. ;

Leyton, Jeffrey, V .

PHARMACEUTICALS, 2021, 14 (07)

[9] Intranuclear protein transduction through a nucleoside salvage pathway [J].

Hansen, James E. ;

Tse, Chung-Ming ;

Chan, Grace ;

Heinze, Emil R. ;

Nishimura, Robert N. ;

Weisbart, Richard H. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (29) :20790-20793

[10] Targeting Cancer with a Lupus Autoantibody [J].

Hansen, James E. ;

Chan, Grace ;

Liu, Yanfeng ;

Hegan, Denise C. ;

Dalal, Shibani ;

Dray, Eloise ;

Kwon, Youngho ;

Xu, Yuanyuan ;

Xu, Xiaohua ;

Peterson-Roth, Elizabeth ;

Geiger, Erik ;

Liu, Yilun ;

Gera, Joseph ;

Sweasy, Joann B. ;

Sung, Patrick ;

Rockwell, Sara ;

Nishimura, Robert N. ;

Weisbart, Richard H. ;

Glazer, Peter M. .

SCIENCE TRANSLATIONAL MEDICINE, 2012, 4 (157)

← 1 2 3 4 →