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«Labelling, quality control and clinical evaluation of monoclonal antibodies for scintigraphy Final report of a co-ordinated research programme ...»

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IAEA-TECDOC-1008

Labelling, quality control and

clinical evaluation of

monoclonal antibodies for

scintigraphy

Final report of a co-ordinated research programme

1991-1996

INTERNATIONAL ATOMIC ENERGY AGENCY /A

March 1997

The IAEA does not normally maintain stocks of reports in this series.

However, microfiche copies of these reports can be obtained from

IN IS Clearinghouse

International Atomic Energy Agency

Wagramerstrasse 5 P.O. Box 100 A-1400 Vienna, Austria Orders should be accompanied by prepayment of Austrian Schillings 100, in the form of a cheque or in the form of IAEA microfiche service coupons which may be ordered separately from the I MIS Clearinghouse.

The originating Section of this publication in the IAEA was:

Industrial Applications and Chemistry Section International Atomic Energy Agency Wagramer Strasse 5 P.O. Box 100 A-1400 Vienna, Austria

LABELLING, QUALITY CONTROL AND CLINICAL EVALUATION OF

MONOCLONAL ANTIBODIES FOR SCINTIGRAPHY

IAEA, VIENNA, 1998 IAEA-TECDOC-1008 ISSN 1011-4289 ©IAEA, 1998 Printed by the IAEA in Austria March 1998

FOREWORD

The discovery of monoclonal antibodies spurred considerable interest in their applications in medical diagnostic techniques soon after their availability. They had been and still continue to be the subject of innumerable publications. They are now extensively used in kits for in vitro immunodiagnostics including radioimmunometric assays.

Monoclonal antibodies also were perceived to offer excellent carriers for radioisotopes for specific in vivo targeting of selected tissues, virtually as a long awaited 'magic bullet'. But the in vivo applications posed many technical challenges including purification of monoclonal antibodies of mouse origin to standards needed for human parenteral use, immune response in humans to mouse immunoglobulin, labelling the radioisotopes, particularly "Tcm, to the antibody molecule without significantly altering its immune properties, slow in vivo kinetics of labelled antibody, its non specific localisation and transchelation of "Tcm and other metallic radionuclides by other serum proteins in vivo. These were, no doubt, formidable challenges but have provided an area of intense and interesting research and development spanning almost a decade. The results of these efforts have contributed significantly to the understanding of the co-ordination chemistry of technetium, synthesis of bifunctional chelates of immunoglobulins to label radionuclides, development of sensitive analytical methods for labelled antibodies and to the overall capabilities of radiopharmaceutical scientists to manipulate bioactive molecules for radiolabelling. Now a few '"In and 99Tcm labelled monoclonal antibody preparations are already available for regular diagnostic use in nuclear medicine.

Realising the potential of labelled monoclonal antibodies for in vivo diagnosis and therapy and the interest in many developing Member States for acquiring expertise in this field the IAEA initiated a co-ordinated research programme in 1991 focusing on "Tcm labelling of antibodies, their quality control and scintigraphic evaluation. Twelve laboratories from Asia, Latin America, Europe and North America participated in this programme which was concluded in 1996. During this programme the participants investigated the "Tc1" labelling of a murine anti-CEA antibody using the method of chelating "Tcm with the free sulfhydryl groups generated by reaction with reducing agents such as mercapto ethanol. During the later part of the programme this method was also extended to "Tcm labelling of hlgG. All the participating laboratories could gain valuable experience in "Tcm antibody labelling techniques and formulation of kits. Many of them have been used in patients by collaborating nuclear medicine specialists with satisfactory results. This report is a compilation of the detailed results obtained by the participating laboratories and includes a summary and assessment of the achievements of the CRP.

The IAEA wishes to thank all the scientists who contributed to the success of the CRP.

EDITORIAL NOTE

In preparing this publication for press, staff of the IAEA have made up the pages from the original manuscript(s). The views expressed do not necessarily reflect those of the IAEA, the governments of the nominating Member States or the nominating organizations.

Throughout the text names of Member States are retained as they were when the text was compiled.

The use of particular designations of countries or territories does not imply any judgement by the publisher, the IAEA, as to the legal status of such countries or territories, of their authorities and institutions or of the delimitation of their boundaries.

The mention of names of specific companies or products (whether or not indicated as registered) does not imply any intention to infringe proprietary rights, nor should it be construed as an endorsement or recommendation on the pan of the IAEA.

CONTENTS

1. INTRODUCTION AND SUMMARY OF RESEARCH RESULTS

1.1. Objectives of the co-ordinated research programme





1.2. Principal outcomes and conclusions of the co-ordinated research programme

1.3. Protocols of the co-ordinated research programme

2. SUMMARY REPORTS OF PARTICIPATING COUNTRIES

2.1. Argentina

2.1.1. Introduction

2.1.2. Materials and methods

2.1.2.1. Direct labelling of ior-CEA-1 antibody

2.1.2.2. Lyophilized kit of IgG

2.1.2.3. Lyophilized kit of ior-CEA-1 antibody

2.1.2.4. Labelling of IgG by photoactivation

2.1.2.5. Indirect labelling of IgG

2.1.3. Results

2.1.3.1. Direct labelling and quality control of ior-CEA-1

2.1.3.2. Labelling and quality control of lyophilized IgG kit

2.1.3.3. Labelling and quality control of lyophilized ior-CEA-1

2.1.3.4. Labelling and quality control of photoactivated IgG

2.1.3.5. Indirect labelling of IgG

2.1.4. Conclusions

2.2. China

2.2.1. Introduction

2.2.2. Materials and methods

2.2.2.1. Direct "Tcm labelling

2.2.2.2. ' "in-labelling based on biotin-avidin conjugation for pre-targeting localization

2.2.3. Results and discussion

2.3. Cuba

2.3.1. Introduction

2.3.2. Materials and methods

2.3.2.1. Monoclonal antibody (MAb)

2.3.2.2. Labelling

2.3.2.3. Quality control

2.3.2.4. Transchelation challenge test

2.3.2.5. Immunoreactivity studies

2.3.2.6. Animal biodistribution study

2.3.2.7. Clinical studies

2.3.3. Results

2.3.4. Discussion

2.3.5. Conclusions

2.4. Greece

2.4.1. Introduction

2.4.2. Materials and methods

2.4.2.1. Radiolabelling

2.4.2.2. Radiochemical quality control

2.4.2.3. Polyacrylamide gel electrophoresis applied to ior-CEA-1

2.4.2.4. Immunoreactivity test

2.4.2.5. Cell binding assay for ior-CEA

2.4.2.6. Stability studies

2.4.2.7. Kit formulation

2.4.2.8. Radiochemistry of the "Tcm-labelled derivatives

2.4.2.9. Mercaptoethanol reduction

2.4.2.10. 2-Iminothiolane coupling

2.4.2.11. Animal studies

2.4.3. Results

2.4.3.1. 2-Mercaptoethanol reduction

2.4.3.2. 2-Iminothiolanecoupling

2.4.3.3. Animal studies

2.4.3.4. Clinical evaluation of human immunoglobulin

2.4.4. Discussion

2.4.5. Conclusions

2.5. Hungary

2.5.1. Introduction

2.5.2. Materials and methods

2.5.2.1. Antibody reduction and purification

2.5.2.2. Radiolabelling

2.5.2.3. Chromatography

2.5.2.4. Polyacrylamide gel electrophoresis

2.5.2.5. Animal biodistribution studies

2.5.2.6. Determination of sulfhydryl concentration

2.5.2.7. Cysteine challenge assay

2.5.2.8. In vitro immunoreactivity determination of "Tcm-MoAb with human granulocytes

2.5.3. Results

2.5.3.1. Chemical-radiochemicalanalysis

2.5.3.2. Biological studies

2.5.3.3. Quality control data of the freeze dried formulations

2.5.4. Conclusions

2.6. India

2.6.1. Introduction

2.6.2. Materials and methods

2.6.2.1. Preparation of "Tcm-labelled hlgG and ior-CEA-1

2.6.2.2. Labelling efficiency and stability of the labelled product

2.6.3. Results

2.6.4. Discussion

2.6.5. Conclusions

2.7. Portugal

2.7.1. Introduction

2.7.2. Materials and methods

2.7.2.1. Antibodies and antigens

2.7.2.2. Radiolabellingmethods

2.7.2.3. Chromatographic systems

2.7.2.4. Immunoreactivity

2.7.2.5. Polyacrylamide gel electrophoresis

2.7.2.6. Animal experiments

2.7.3. Results and discussion

2.7.4. Conclusions

2.8. Thailand

2.8.1. Introduction

2.8.2. Materials and methods

2.8.2.1. Antibodies and human immunoglobulins

2.8.2.2. Reduction of MoAb and h!gG

2.8.2.3. Stannous kits for "Tcm reduction

2.8.2.4. Radiolabelling

2.8.2.5. Immunoreactivity assay

2.8.2.6. Cysteine challenge assay

2.8.2.7. Animal biodistribution study

2.8.2.8. Limulus amoebocyte lysate (LAL) assay

2.8.3. Results

2.8.3.1. Stoichiometry in wTcm-labelling of MAbs and hlgGs

2.8.3.2. Characterization of "TV-labelled MAbs and hlgs

2.8.3.3. Development of instant kits and assessment of kit performances..................95 2.8.4. Discussion

2.8.5. Conclusions

ANNEX: RECOMMENDED PROCEDURES FOR RADIOLABELLING OF ANTIBODY

(ior-CEA-1) WITH "tcmAND ITS EVALUATION

BIBLIOGRAPHY

PUBLICATIONS RESULTING FROM THE PROJECT WORK

ABBREVIATIONS

PARTICIPANTS IN THE CO-ORDINATED RESEARCH PROGRAMME

1. INTRODUCTION AND SUMMARY OF RESEARCH RESULTS

1.1. OBJECTIVES OF THE CO-ORDINATED RESEARCH PROGRAMME

The Co-ordinated Research Programme (CRP) on Labelling, Quality Control and Clinical Evaluation of Monoclonal Antibodies for Scintigraphy was organized as a follow-up of the recommendations of a consultants meeting organized by the IAEA in Vienna in August 1988. It was generally concluded in the meeting that radiolabelled monoclonal antibodies could be potentially useful for the scintigraphic detection of malignancies and labelling methods reported at that time showed sufficient promise for further development and absorption by laboratories in developing countries. The other recommendations made by the consultants with regard to the

CRP were:

Methods for 131I labelling of monoclonal antibodies (MoAb) are fairly well developed and (a) could form part of the proposed CRP. However, considering the availability, cost and imaging properties, "Tcm is universally recognized as the superior radiolabel for most imaging studies. Methods for "Tcm labelling were under development in many laboratories and promising results were being reported, particularly using the antibody reduction method.

These developments should be carefully watched and suitably incorporated in the proposed CRP work plan;

(b) It was recognized that monoclonal antibody against carcino embryonic antigen (CEA), which is elevated in about 90% of colorectal cancer cases and also in significant numbers of other malignancies including breast, gastric, lung and medullary thyroid carcinomas could be chosen for radiolabelling under the CRP since it may lead to an agent potentially useful for their diagnosis and follow up. Anti-CEA monoclonal antibodies had also the advantage in their availability from several sources;

Twelve scientists from reputable laboratories from both developing and developed countries participated in the CRP organized during the period 1991-1996. During the course of the CRP four research co-ordination meetings were held where the participants presented and discussed the outcome of their investigations. The location and dates of the meetings wee: Kuala Lumpur, Malaysia, 9-13 September 1991, Cambridge, United Kingdom, 15-19 March 1993, Sydney, Australia 19-22 October 1994 and Athens, Greece, 10-14 June 1996.

Monoclonal antibodies

In the beginning of the CRP an anti-adenocarcinoma murine IgG antibody of Biomira (Edmonton, Canada) designated as MoAb 170 was used. Although not an anti-CEA antibody, MoAb 170 was reported to be useful in the detection of gynecologic adenocarcinomas, breast carcinoma, and lung carcinoma.

Valuable experience was gained by all participants using MoAb 170 eventhough some unexpected problems came in the way of labelling and evaluation of this antibody. The antigen specifically reacting with MoAb 170 was not available, presumably because of its rapid degradation following isolation. Hence it would not be possible for participants in the CRP to determine the immunoreactivity of their labelled MoAb 170. Furthermore, although the MoAb 170 was reported to be radiolabelled successfully with "Tcm by colleagues at Biomira using a proprietary labelling method, it proved difficult to label this antibody with the mercaptoethanol reduction method. In order to achieve labelling, the concentration of mercaptoethanol had to be raised by about a factor of five. Possibly because of these harsh reducing conditions, the immunoreactivity of the labelled MoAb 170 was reduced to about 16% of that of the native antibody. Because of these problems, MoAb 170 was given up and a decision was made to look for another monoclonal antibody.

A murine anti-CEA monoclonal antibody of the Center of Molecular Investigation, Havana, Cuba designated as ior-CEA-1 was made available subsequently. Ior-CEA-1 is an IgGl MoAb secreted by the F6/1B2-D2 hybridoma obtained from the fusion of the P3/X63 Ag8 653 murine myeloma with splenic lymphocytes of a Balb/c mouse immunized with CEA purified from a liver metastases of a colon adenocarcinoma. The ior-CEA-1 MoAb is purified from mouse ascitic fluid by affinity chromatography in protein A sepharose. This antibody was provided in several lots and in sufficient quantities with which labelling methods were standardized and in many cases, clinical trials were performed.



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