Preparation, biodistribution and dosimetry of copper-64-labeled anti- colorectal carcinoma monoclonal antibody fragments 1A3-F(ab')2

C. J. Anderson; S. W. Schwarz; J. M. Connett; P. D. Cutler; Wu Guo Li Wu Guo; C. J. Germain; G. W. Philpott; K. R. Zinn; D. P. Greiner; C. F. Meares; M. J. Welch

Preparation, biodistribution and dosimetry of copper-64-labeled anti- colorectal carcinoma monoclonal antibody fragments 1A3-F(ab')₂

C. J. Anderson, S. W. Schwarz, J. M. Connett, P. D. Cutler, Wu Guo Li Wu Guo, C. J. Germain, G. W. Philpott, K. R. Zinn, D. P. Greiner, C. F. Meares, M. J. Welch

Division of Research Imaging Facilities

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

57 Scopus citations

Abstract

Antibody fragments labeled with a radiometal using bifunctional chelates generally undergo renal clearance followed by trapping of the metabolites, leading to high radiation doses to the kidneys. Copper-64-labeled BAT-2IT- 1A3-F(ab')₂ was recently reported to accumulate in colorectal tumors in an animal model, however, kidney uptake was also high. In this study, the preparation of ⁶⁴Cu-BAT-2IT-1A3-F(ab')₂ was optimized to reduce the renal uptake. Methods: The bifunctional chelate 6-bromoacetamidobenzyl-1,4,8,11- tetraazacyclotetradecane-N,N',N',N''-tetraacetic acid (BAT) was conjugated to 1A3-F(ab')₂ using the linking agent 2-iminothiolane (2IT). The conjugation reaction produced 20% of a lower molecular weight (molecular weight) impurity found to be TETA-1A3-Fab'. The conjugation procedure was optimized to include FPLC purification of the BAT-2IT-1A3-F(ab')₂ from TETA-1A3-Fab' after conjugation prior to labeling with ⁶⁴Cu. The biodistribution of ⁶⁴Cu- labeled FPLC-purified and unpurified conjugates was determined in normal Sprague-Dawley rats and tumor-bearing Golden Syrian hamsters. Human absorbed doses were calculated from rat biodistribution data and PET imaging of a baboon. Results: Upon FPLC purification of the BAT-2IT-1A3-F(ab')₂, the immunoreactivity of ⁶⁴Cu-labeled 1A3-F(ab')₂ was significantly improved over that of non-FPLC-purified ⁶⁴Cu-BAT-2IT-1A3-F(ab')₂, and the kidney uptake was decreased in normal rats. The biodistribution in hamsters showed some improvement in both tumor uptake and kidney clearance with FPLC-purified ⁶⁴Cu-BAT-2IT-1A3-F(ab')₂. Conclusion: The improved dosimetry of ⁶⁴Cu- labeled FPLC purified BAT-2IT-1A3-F(ab')₂ should more readily allow this agent to be investigated clinically to image colorectal cancer using PET.

Original language	English
Pages (from-to)	850-858
Number of pages	9
Journal	Journal of Nuclear Medicine
Volume	36
Issue number	5
State	Published - 1995

Keywords

Monoclonal antibody fragments
animal biodistribution
colorectal carcinoma
copper-64
dosimetry

Cite this

@article{cc8ed96eac894d94acaf1dcc9bce7e4f,

title = "Preparation, biodistribution and dosimetry of copper-64-labeled anti- colorectal carcinoma monoclonal antibody fragments 1A3-F(ab')2",

abstract = "Antibody fragments labeled with a radiometal using bifunctional chelates generally undergo renal clearance followed by trapping of the metabolites, leading to high radiation doses to the kidneys. Copper-64-labeled BAT-2IT- 1A3-F(ab')2 was recently reported to accumulate in colorectal tumors in an animal model, however, kidney uptake was also high. In this study, the preparation of 64Cu-BAT-2IT-1A3-F(ab')2 was optimized to reduce the renal uptake. Methods: The bifunctional chelate 6-bromoacetamidobenzyl-1,4,8,11- tetraazacyclotetradecane-N,N',N',N''-tetraacetic acid (BAT) was conjugated to 1A3-F(ab')2 using the linking agent 2-iminothiolane (2IT). The conjugation reaction produced 20% of a lower molecular weight (molecular weight) impurity found to be TETA-1A3-Fab'. The conjugation procedure was optimized to include FPLC purification of the BAT-2IT-1A3-F(ab')2 from TETA-1A3-Fab' after conjugation prior to labeling with 64Cu. The biodistribution of 64Cu- labeled FPLC-purified and unpurified conjugates was determined in normal Sprague-Dawley rats and tumor-bearing Golden Syrian hamsters. Human absorbed doses were calculated from rat biodistribution data and PET imaging of a baboon. Results: Upon FPLC purification of the BAT-2IT-1A3-F(ab')2, the immunoreactivity of 64Cu-labeled 1A3-F(ab')2 was significantly improved over that of non-FPLC-purified 64Cu-BAT-2IT-1A3-F(ab')2, and the kidney uptake was decreased in normal rats. The biodistribution in hamsters showed some improvement in both tumor uptake and kidney clearance with FPLC-purified 64Cu-BAT-2IT-1A3-F(ab')2. Conclusion: The improved dosimetry of 64Cu- labeled FPLC purified BAT-2IT-1A3-F(ab')2 should more readily allow this agent to be investigated clinically to image colorectal cancer using PET.",

keywords = "Monoclonal antibody fragments, animal biodistribution, colorectal carcinoma, copper-64, dosimetry",

author = "Anderson, {C. J.} and Schwarz, {S. W.} and Connett, {J. M.} and Cutler, {P. D.} and {Li Wu Guo}, {Wu Guo} and Germain, {C. J.} and Philpott, {G. W.} and Zinn, {K. R.} and Greiner, {D. P.} and Meares, {C. F.} and Welch, {M. J.}",

year = "1995",

language = "English",

volume = "36",

pages = "850--858",

journal = "Journal of Nuclear Medicine",

issn = "0161-5505",

number = "5",

}

TY - JOUR

T1 - Preparation, biodistribution and dosimetry of copper-64-labeled anti- colorectal carcinoma monoclonal antibody fragments 1A3-F(ab')2

AU - Anderson, C. J.

AU - Schwarz, S. W.

AU - Connett, J. M.

AU - Cutler, P. D.

AU - Li Wu Guo, Wu Guo

AU - Germain, C. J.

AU - Philpott, G. W.

AU - Zinn, K. R.

AU - Greiner, D. P.

AU - Meares, C. F.

AU - Welch, M. J.

PY - 1995

Y1 - 1995

N2 - Antibody fragments labeled with a radiometal using bifunctional chelates generally undergo renal clearance followed by trapping of the metabolites, leading to high radiation doses to the kidneys. Copper-64-labeled BAT-2IT- 1A3-F(ab')2 was recently reported to accumulate in colorectal tumors in an animal model, however, kidney uptake was also high. In this study, the preparation of 64Cu-BAT-2IT-1A3-F(ab')2 was optimized to reduce the renal uptake. Methods: The bifunctional chelate 6-bromoacetamidobenzyl-1,4,8,11- tetraazacyclotetradecane-N,N',N',N''-tetraacetic acid (BAT) was conjugated to 1A3-F(ab')2 using the linking agent 2-iminothiolane (2IT). The conjugation reaction produced 20% of a lower molecular weight (molecular weight) impurity found to be TETA-1A3-Fab'. The conjugation procedure was optimized to include FPLC purification of the BAT-2IT-1A3-F(ab')2 from TETA-1A3-Fab' after conjugation prior to labeling with 64Cu. The biodistribution of 64Cu- labeled FPLC-purified and unpurified conjugates was determined in normal Sprague-Dawley rats and tumor-bearing Golden Syrian hamsters. Human absorbed doses were calculated from rat biodistribution data and PET imaging of a baboon. Results: Upon FPLC purification of the BAT-2IT-1A3-F(ab')2, the immunoreactivity of 64Cu-labeled 1A3-F(ab')2 was significantly improved over that of non-FPLC-purified 64Cu-BAT-2IT-1A3-F(ab')2, and the kidney uptake was decreased in normal rats. The biodistribution in hamsters showed some improvement in both tumor uptake and kidney clearance with FPLC-purified 64Cu-BAT-2IT-1A3-F(ab')2. Conclusion: The improved dosimetry of 64Cu- labeled FPLC purified BAT-2IT-1A3-F(ab')2 should more readily allow this agent to be investigated clinically to image colorectal cancer using PET.

AB - Antibody fragments labeled with a radiometal using bifunctional chelates generally undergo renal clearance followed by trapping of the metabolites, leading to high radiation doses to the kidneys. Copper-64-labeled BAT-2IT- 1A3-F(ab')2 was recently reported to accumulate in colorectal tumors in an animal model, however, kidney uptake was also high. In this study, the preparation of 64Cu-BAT-2IT-1A3-F(ab')2 was optimized to reduce the renal uptake. Methods: The bifunctional chelate 6-bromoacetamidobenzyl-1,4,8,11- tetraazacyclotetradecane-N,N',N',N''-tetraacetic acid (BAT) was conjugated to 1A3-F(ab')2 using the linking agent 2-iminothiolane (2IT). The conjugation reaction produced 20% of a lower molecular weight (molecular weight) impurity found to be TETA-1A3-Fab'. The conjugation procedure was optimized to include FPLC purification of the BAT-2IT-1A3-F(ab')2 from TETA-1A3-Fab' after conjugation prior to labeling with 64Cu. The biodistribution of 64Cu- labeled FPLC-purified and unpurified conjugates was determined in normal Sprague-Dawley rats and tumor-bearing Golden Syrian hamsters. Human absorbed doses were calculated from rat biodistribution data and PET imaging of a baboon. Results: Upon FPLC purification of the BAT-2IT-1A3-F(ab')2, the immunoreactivity of 64Cu-labeled 1A3-F(ab')2 was significantly improved over that of non-FPLC-purified 64Cu-BAT-2IT-1A3-F(ab')2, and the kidney uptake was decreased in normal rats. The biodistribution in hamsters showed some improvement in both tumor uptake and kidney clearance with FPLC-purified 64Cu-BAT-2IT-1A3-F(ab')2. Conclusion: The improved dosimetry of 64Cu- labeled FPLC purified BAT-2IT-1A3-F(ab')2 should more readily allow this agent to be investigated clinically to image colorectal cancer using PET.

KW - Monoclonal antibody fragments

KW - animal biodistribution

KW - colorectal carcinoma

KW - copper-64

KW - dosimetry

UR - http://www.scopus.com/inward/record.url?scp=0029069640&partnerID=8YFLogxK

M3 - Article

C2 - 7738663

AN - SCOPUS:0029069640

VL - 36

SP - 850

EP - 858

JO - Journal of Nuclear Medicine

JF - Journal of Nuclear Medicine

SN - 0161-5505

IS - 5

ER -

Preparation, biodistribution and dosimetry of copper-64-labeled anti- colorectal carcinoma monoclonal antibody fragments 1A3-F(ab')₂

Abstract

Keywords

Other files and links

Fingerprint

Cite this