Pharmacokinetics and biodistribution of a light-chain-shuffled CC49 single-chain Fv antibody construct

Gabriela Pavlinkova, David Colcher, Barbara J M Booth, Apollina Goel, Surinder Kumar Batra

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Murine monoclonal antibodies to tumor-associated glycoprotein 72 (anti- TAG-72 mAb B72.3 and CC49) are among the most extensively studied mAb for immunotherapy of adenocarcinomas. They have been used clinically to localize primary and metastatic tumor sites; however, murine mAb generally induce potent human anti-(mouse antibody) responses. The immunogenicity of murine mAb can be minimized by genetic humanization of these antibodies, where non- human regions are replaced by the corresponding human sequences or complementary determining regions are grafted into the human framework regions. We have developed a humanized CC49 single-chain antibody construct (hu/muCC49 scFv) by replacing the murine CC49 variable light chain with the human subgroup IV germline variable light chain (Hum4 V(L)). The major advantages of scFv molecules are their excellent penetration into the tumor tissue, rapid clearance rate, and much lower exposure to normal organs, especially bone marrow, than occur with intact antibody. The biochemical properties of hu/muCC49 scFv were compared to those of the murine CC49 scFv (muCC49 scFv). The association constants (K(a)) for hu/muCC49 and muCC49 constructs were 1.1 x 106 M-1 and 1.4 x 106 M-1 respectively. Pharmacokinetic studies in mice showed similar rapid blood and whole-body clearance with a half-life of 6 min for both scFv. The biodistribution studies demonstrated equivalent tumor targeting to human colon carcinoma xenografts for muCC49 and hu/muCC49 scFv. These results indicate that the human variable light-chain subgroup IV can be used for the development of humanized or human immunoglobulin molecules potentially useful in both diagnostic and therapeutic applications with TAG-72-positive tumors.

Original languageEnglish (US)
Pages (from-to)267-275
Number of pages9
JournalCancer Immunology Immunotherapy
Volume49
Issue number4-5
DOIs
StatePublished - Jan 1 2000

Fingerprint

Single-Chain Antibodies
Pharmacokinetics
Light
Neoplasms
Antibodies
Heterografts
Immunotherapy
Antibody Formation
Half-Life
Immunoglobulins
Anti-Idiotypic Antibodies
Colon
Adenocarcinoma
Bone Marrow
Monoclonal Antibodies
Carcinoma

Keywords

  • Antibody engineering
  • Human colon cancer xenografts
  • Monoclonal antibodies
  • Recombinant antibody
  • Single-chain antibodies

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

Cite this

Pharmacokinetics and biodistribution of a light-chain-shuffled CC49 single-chain Fv antibody construct. / Pavlinkova, Gabriela; Colcher, David; Booth, Barbara J M; Goel, Apollina; Batra, Surinder Kumar.

In: Cancer Immunology Immunotherapy, Vol. 49, No. 4-5, 01.01.2000, p. 267-275.

Research output: Contribution to journalArticle

Pavlinkova, Gabriela ; Colcher, David ; Booth, Barbara J M ; Goel, Apollina ; Batra, Surinder Kumar. / Pharmacokinetics and biodistribution of a light-chain-shuffled CC49 single-chain Fv antibody construct. In: Cancer Immunology Immunotherapy. 2000 ; Vol. 49, No. 4-5. pp. 267-275.
@article{fdc84e2b8bca4e1f94692fe2f83a15b8,
title = "Pharmacokinetics and biodistribution of a light-chain-shuffled CC49 single-chain Fv antibody construct",
abstract = "Murine monoclonal antibodies to tumor-associated glycoprotein 72 (anti- TAG-72 mAb B72.3 and CC49) are among the most extensively studied mAb for immunotherapy of adenocarcinomas. They have been used clinically to localize primary and metastatic tumor sites; however, murine mAb generally induce potent human anti-(mouse antibody) responses. The immunogenicity of murine mAb can be minimized by genetic humanization of these antibodies, where non- human regions are replaced by the corresponding human sequences or complementary determining regions are grafted into the human framework regions. We have developed a humanized CC49 single-chain antibody construct (hu/muCC49 scFv) by replacing the murine CC49 variable light chain with the human subgroup IV germline variable light chain (Hum4 V(L)). The major advantages of scFv molecules are their excellent penetration into the tumor tissue, rapid clearance rate, and much lower exposure to normal organs, especially bone marrow, than occur with intact antibody. The biochemical properties of hu/muCC49 scFv were compared to those of the murine CC49 scFv (muCC49 scFv). The association constants (K(a)) for hu/muCC49 and muCC49 constructs were 1.1 x 106 M-1 and 1.4 x 106 M-1 respectively. Pharmacokinetic studies in mice showed similar rapid blood and whole-body clearance with a half-life of 6 min for both scFv. The biodistribution studies demonstrated equivalent tumor targeting to human colon carcinoma xenografts for muCC49 and hu/muCC49 scFv. These results indicate that the human variable light-chain subgroup IV can be used for the development of humanized or human immunoglobulin molecules potentially useful in both diagnostic and therapeutic applications with TAG-72-positive tumors.",
keywords = "Antibody engineering, Human colon cancer xenografts, Monoclonal antibodies, Recombinant antibody, Single-chain antibodies",
author = "Gabriela Pavlinkova and David Colcher and Booth, {Barbara J M} and Apollina Goel and Batra, {Surinder Kumar}",
year = "2000",
month = "1",
day = "1",
doi = "10.1007/s002620000108",
language = "English (US)",
volume = "49",
pages = "267--275",
journal = "Cancer Immunology and Immunotherapy",
issn = "0340-7004",
publisher = "Springer Science and Business Media Deutschland GmbH",
number = "4-5",

}

TY - JOUR

T1 - Pharmacokinetics and biodistribution of a light-chain-shuffled CC49 single-chain Fv antibody construct

AU - Pavlinkova, Gabriela

AU - Colcher, David

AU - Booth, Barbara J M

AU - Goel, Apollina

AU - Batra, Surinder Kumar

PY - 2000/1/1

Y1 - 2000/1/1

N2 - Murine monoclonal antibodies to tumor-associated glycoprotein 72 (anti- TAG-72 mAb B72.3 and CC49) are among the most extensively studied mAb for immunotherapy of adenocarcinomas. They have been used clinically to localize primary and metastatic tumor sites; however, murine mAb generally induce potent human anti-(mouse antibody) responses. The immunogenicity of murine mAb can be minimized by genetic humanization of these antibodies, where non- human regions are replaced by the corresponding human sequences or complementary determining regions are grafted into the human framework regions. We have developed a humanized CC49 single-chain antibody construct (hu/muCC49 scFv) by replacing the murine CC49 variable light chain with the human subgroup IV germline variable light chain (Hum4 V(L)). The major advantages of scFv molecules are their excellent penetration into the tumor tissue, rapid clearance rate, and much lower exposure to normal organs, especially bone marrow, than occur with intact antibody. The biochemical properties of hu/muCC49 scFv were compared to those of the murine CC49 scFv (muCC49 scFv). The association constants (K(a)) for hu/muCC49 and muCC49 constructs were 1.1 x 106 M-1 and 1.4 x 106 M-1 respectively. Pharmacokinetic studies in mice showed similar rapid blood and whole-body clearance with a half-life of 6 min for both scFv. The biodistribution studies demonstrated equivalent tumor targeting to human colon carcinoma xenografts for muCC49 and hu/muCC49 scFv. These results indicate that the human variable light-chain subgroup IV can be used for the development of humanized or human immunoglobulin molecules potentially useful in both diagnostic and therapeutic applications with TAG-72-positive tumors.

AB - Murine monoclonal antibodies to tumor-associated glycoprotein 72 (anti- TAG-72 mAb B72.3 and CC49) are among the most extensively studied mAb for immunotherapy of adenocarcinomas. They have been used clinically to localize primary and metastatic tumor sites; however, murine mAb generally induce potent human anti-(mouse antibody) responses. The immunogenicity of murine mAb can be minimized by genetic humanization of these antibodies, where non- human regions are replaced by the corresponding human sequences or complementary determining regions are grafted into the human framework regions. We have developed a humanized CC49 single-chain antibody construct (hu/muCC49 scFv) by replacing the murine CC49 variable light chain with the human subgroup IV germline variable light chain (Hum4 V(L)). The major advantages of scFv molecules are their excellent penetration into the tumor tissue, rapid clearance rate, and much lower exposure to normal organs, especially bone marrow, than occur with intact antibody. The biochemical properties of hu/muCC49 scFv were compared to those of the murine CC49 scFv (muCC49 scFv). The association constants (K(a)) for hu/muCC49 and muCC49 constructs were 1.1 x 106 M-1 and 1.4 x 106 M-1 respectively. Pharmacokinetic studies in mice showed similar rapid blood and whole-body clearance with a half-life of 6 min for both scFv. The biodistribution studies demonstrated equivalent tumor targeting to human colon carcinoma xenografts for muCC49 and hu/muCC49 scFv. These results indicate that the human variable light-chain subgroup IV can be used for the development of humanized or human immunoglobulin molecules potentially useful in both diagnostic and therapeutic applications with TAG-72-positive tumors.

KW - Antibody engineering

KW - Human colon cancer xenografts

KW - Monoclonal antibodies

KW - Recombinant antibody

KW - Single-chain antibodies

UR - http://www.scopus.com/inward/record.url?scp=0033930249&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033930249&partnerID=8YFLogxK

U2 - 10.1007/s002620000108

DO - 10.1007/s002620000108

M3 - Article

C2 - 10941910

AN - SCOPUS:0033930249

VL - 49

SP - 267

EP - 275

JO - Cancer Immunology and Immunotherapy

JF - Cancer Immunology and Immunotherapy

SN - 0340-7004

IS - 4-5

ER -