Bispecific adapter-mediated retargeting of a receptor-restricted HSV-1 vector to CEA-bearing tumor cells

Hyunjung Baek; Hiroaki Uchida; Kyungok Jun; Jae Hong Kim; Masahide Kuroki; Justus B. Cohen; Joseph C. Glorioso; Heechung Kwon

doi:10.1038/mt.2010.207

Bispecific adapter-mediated retargeting of a receptor-restricted HSV-1 vector to CEA-bearing tumor cells

Hyunjung Baek, Hiroaki Uchida, Kyungok Jun, Jae Hong Kim, Masahide Kuroki, Justus B. Cohen, Joseph C. Glorioso, Heechung Kwon

Research output: Contribution to journal › Article › peer-review

23 Citations (Scopus)

Abstract

The safety and efficacy of viral therapies for solid tumors can be enhanced by redirecting the virus infection to tumor-specific cell-surface markers. Successful retargeting of herpes simplex virus type 1 (HSV-1) has been achieved using vectors that carry a modified envelope glycoprotein D (gD) engineered to interact directly with novel receptors. In addition, soluble bridging molecules (adapters) have been used to link gD indirectly to cell-specific receptors. Here, we describe the development of an adapter connecting gD to the common tumor antigen carcinoembryonic antigen (CEA). The adapter consisted of a CEA-specific single-chain antibody fused to the gD-binding region of the gD receptor, herpes virus entry mediator (HVEM). We used this adapter in combination with a vector that is detargeted for recognition of the widely expressed gD receptor nectin-1, but retains an intact binding region for the less common HVEM. We show that the adapter enabled infection of HSV-resistant Chinese hamster ovary (CHO) cells expressing ectopic CEA and nectin-1/CEA-bearing human gastric carcinoma cells that are resistant to the vector alone. We observed cell-to-cell spread following adapter-mediated infection in vitro and reduced tumor growth in vivo, indicating that this method of vector retargeting may provide a novel strategy for tumor-specific delivery of tumoricidal HSV.

Original language	English
Pages (from-to)	507-514
Number of pages	8
Journal	Molecular Therapy
Volume	19
Issue number	3
DOIs	https://doi.org/10.1038/mt.2010.207
Publication status	Published - 2011 Mar

Bibliographical note

Funding Information:
We thank Patricia Spear (Northwestern University) for pBEC14 and William Goins (University of Pittsburgh) for helpful discussions. This work was supported by grants 0065410, 0002125 and 0093737 to H.K. from the Korea Science and Engineering Foundation (KOSEF) funded by the Korean government (MEST), and by NIH grants CA119298, NS40923, and DK044935 to J.C.G. J.C.G. is an inventor of patents related to HSV technology and owns equity in a publicly traded company, Diamyd Medical AB based in Stockholm, Sweden, that is evaluating HSV gene therapy applications for the treatment of chronic pain.

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Pharmacology
Drug Discovery

Access to Document

10.1038/mt.2010.207

Cite this

@article{dab74fd5fc4a494789de240b0d22928d,

title = "Bispecific adapter-mediated retargeting of a receptor-restricted HSV-1 vector to CEA-bearing tumor cells",

abstract = "The safety and efficacy of viral therapies for solid tumors can be enhanced by redirecting the virus infection to tumor-specific cell-surface markers. Successful retargeting of herpes simplex virus type 1 (HSV-1) has been achieved using vectors that carry a modified envelope glycoprotein D (gD) engineered to interact directly with novel receptors. In addition, soluble bridging molecules (adapters) have been used to link gD indirectly to cell-specific receptors. Here, we describe the development of an adapter connecting gD to the common tumor antigen carcinoembryonic antigen (CEA). The adapter consisted of a CEA-specific single-chain antibody fused to the gD-binding region of the gD receptor, herpes virus entry mediator (HVEM). We used this adapter in combination with a vector that is detargeted for recognition of the widely expressed gD receptor nectin-1, but retains an intact binding region for the less common HVEM. We show that the adapter enabled infection of HSV-resistant Chinese hamster ovary (CHO) cells expressing ectopic CEA and nectin-1/CEA-bearing human gastric carcinoma cells that are resistant to the vector alone. We observed cell-to-cell spread following adapter-mediated infection in vitro and reduced tumor growth in vivo, indicating that this method of vector retargeting may provide a novel strategy for tumor-specific delivery of tumoricidal HSV.",

author = "Hyunjung Baek and Hiroaki Uchida and Kyungok Jun and Kim, {Jae Hong} and Masahide Kuroki and Cohen, {Justus B.} and Glorioso, {Joseph C.} and Heechung Kwon",

note = "Funding Information: We thank Patricia Spear (Northwestern University) for pBEC14 and William Goins (University of Pittsburgh) for helpful discussions. This work was supported by grants 0065410, 0002125 and 0093737 to H.K. from the Korea Science and Engineering Foundation (KOSEF) funded by the Korean government (MEST), and by NIH grants CA119298, NS40923, and DK044935 to J.C.G. J.C.G. is an inventor of patents related to HSV technology and owns equity in a publicly traded company, Diamyd Medical AB based in Stockholm, Sweden, that is evaluating HSV gene therapy applications for the treatment of chronic pain.",

year = "2011",

month = mar,

doi = "10.1038/mt.2010.207",

language = "English",

volume = "19",

pages = "507--514",

journal = "Molecular Therapy",

issn = "1525-0016",

publisher = "Cell Press",

number = "3",

}

TY - JOUR

T1 - Bispecific adapter-mediated retargeting of a receptor-restricted HSV-1 vector to CEA-bearing tumor cells

AU - Baek, Hyunjung

AU - Uchida, Hiroaki

AU - Jun, Kyungok

AU - Kim, Jae Hong

AU - Kuroki, Masahide

AU - Cohen, Justus B.

AU - Glorioso, Joseph C.

AU - Kwon, Heechung

N1 - Funding Information: We thank Patricia Spear (Northwestern University) for pBEC14 and William Goins (University of Pittsburgh) for helpful discussions. This work was supported by grants 0065410, 0002125 and 0093737 to H.K. from the Korea Science and Engineering Foundation (KOSEF) funded by the Korean government (MEST), and by NIH grants CA119298, NS40923, and DK044935 to J.C.G. J.C.G. is an inventor of patents related to HSV technology and owns equity in a publicly traded company, Diamyd Medical AB based in Stockholm, Sweden, that is evaluating HSV gene therapy applications for the treatment of chronic pain.

PY - 2011/3

Y1 - 2011/3

N2 - The safety and efficacy of viral therapies for solid tumors can be enhanced by redirecting the virus infection to tumor-specific cell-surface markers. Successful retargeting of herpes simplex virus type 1 (HSV-1) has been achieved using vectors that carry a modified envelope glycoprotein D (gD) engineered to interact directly with novel receptors. In addition, soluble bridging molecules (adapters) have been used to link gD indirectly to cell-specific receptors. Here, we describe the development of an adapter connecting gD to the common tumor antigen carcinoembryonic antigen (CEA). The adapter consisted of a CEA-specific single-chain antibody fused to the gD-binding region of the gD receptor, herpes virus entry mediator (HVEM). We used this adapter in combination with a vector that is detargeted for recognition of the widely expressed gD receptor nectin-1, but retains an intact binding region for the less common HVEM. We show that the adapter enabled infection of HSV-resistant Chinese hamster ovary (CHO) cells expressing ectopic CEA and nectin-1/CEA-bearing human gastric carcinoma cells that are resistant to the vector alone. We observed cell-to-cell spread following adapter-mediated infection in vitro and reduced tumor growth in vivo, indicating that this method of vector retargeting may provide a novel strategy for tumor-specific delivery of tumoricidal HSV.

AB - The safety and efficacy of viral therapies for solid tumors can be enhanced by redirecting the virus infection to tumor-specific cell-surface markers. Successful retargeting of herpes simplex virus type 1 (HSV-1) has been achieved using vectors that carry a modified envelope glycoprotein D (gD) engineered to interact directly with novel receptors. In addition, soluble bridging molecules (adapters) have been used to link gD indirectly to cell-specific receptors. Here, we describe the development of an adapter connecting gD to the common tumor antigen carcinoembryonic antigen (CEA). The adapter consisted of a CEA-specific single-chain antibody fused to the gD-binding region of the gD receptor, herpes virus entry mediator (HVEM). We used this adapter in combination with a vector that is detargeted for recognition of the widely expressed gD receptor nectin-1, but retains an intact binding region for the less common HVEM. We show that the adapter enabled infection of HSV-resistant Chinese hamster ovary (CHO) cells expressing ectopic CEA and nectin-1/CEA-bearing human gastric carcinoma cells that are resistant to the vector alone. We observed cell-to-cell spread following adapter-mediated infection in vitro and reduced tumor growth in vivo, indicating that this method of vector retargeting may provide a novel strategy for tumor-specific delivery of tumoricidal HSV.

UR - http://www.scopus.com/inward/record.url?scp=79952190298&partnerID=8YFLogxK

U2 - 10.1038/mt.2010.207

DO - 10.1038/mt.2010.207

M3 - Article

C2 - 20924362

AN - SCOPUS:79952190298

SN - 1525-0016

VL - 19

SP - 507

EP - 514

JO - Molecular Therapy

JF - Molecular Therapy

IS - 3

ER -

Bispecific adapter-mediated retargeting of a receptor-restricted HSV-1 vector to CEA-bearing tumor cells

Abstract

Bibliographical note

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this