Tumour targeting of humanised cross-linked divalent-fab′ antibody fragments: a clinical phase I/II study

Antibody engineering has made it possible to design antibodies with optimal characteristics for delivery of radionuclides for tumour imaging and therapy. A humanised divalent-Fab′ cross-linked with a bis-maleimide linker referred to as humanised divalent-Fab′ maleimide was produced as a result of this design process. It is a humanised divalent antibody with no Fc, which can be produced in bacteria and has enhanced stability compared with F(ab′)2. Here we describe a clinical study in patients with colorectal cancer using humanised divalent-Fab′ maleimide generated from the anti-carcinoembryonic antigen antibody A5B7 radiolabelled with iodine-131. Ten patients received an i.v. injection of iodine-131-labelled A5B7 humanised divalent-Fab′ maleimide, and positive tumour images were obtained by gamma camera imaging in eight patients with known lesions, and one previously undetected lesion was identified. True negative results were obtained in two patients without tumour. Area under the curve analysis of serial blood gamma counting and gamma camera images showed a higher tumour to blood ratio compared to A5B7 mF(ab′)2 used previously in the clinic, implying this new molecule may be superior for radioimmunotherapy. MIRD dose calculations showed a relatively high radiation dose to the kidney, which may limit the amount of activity that could be administered in radioimmunotherapy. However the reduction in immunogenicity was also a major advantage for A5B7 humanised divalent-Fab′ maleimide over murine versions of this antibody suggesting that humanised divalent-Fab′ maleimide should be a useful vehicle for repeated therapies.

• Publication year

  2002

• Venue

  British Journal of Cancer

• Publication date

  2002-05-06

• Fields of study

  Medicine

• Identifiers
  DOI 10.1038/sj.bjc.6600198PMID 11986771PMCID 2375360
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2007cited by this paper
• Accurate quantification of131I distribution by gamma camera imaging

  2004cited by this paper
• Improved tumour targeting of di-Fab ' fragments modified with polyethylene glycol

  1999cited by this paper
• Factors influencing the pharmacokinetics, dosimetry, and diagnostic accuracy of radioimmunodetection and radioimmunotherapy of carcinoembryonic antigen-expressing tumors.

  1996cited by this paper
• Late renal function following whole abdominal irradiation.

  1996cited by this paper
• Preparation, characterisation and tumour targeting of cross-linked divalent and trivalent anti-tumour Fab' fragments.

  1996cited by this paper
• Clinical evidence of efficient tumor targetting based on single–chain Fv antibody selected from a combinatorial library

  1996cited by this paper
• Comprehensive pharmacokinetics of a humanized antibody and analysis of residual anti-idiotypic responses.

  1995cited by this paper
• Purification of bacterially expressed single chain Fv antibodies for clinical applications using metal chelate chromatography.

  1995cited by this paper
• Circulating antigen: bad or good for immunoscintigraphy?

  1995cited by this paper
• Clinical trials with CAMPATH-I and other monoclonal antibodies.

  1995cited by this paper
• Evaluation of a complementarity-determining region-grafted (humanized) anti-carcinoembryonic antigen monoclonal antibody in preclinical and clinical studies.

  1995cited by this paper
• Treatment of non-Hodgkin's lymphoma with radiolabeled murine, chimeric, or humanized LL2, an anti-CD22 monoclonal antibody.

  1995cited by this paper
• Antigen-specific human antibodies from mice comprising four distinct genetic modifications

  1994cited by this paper
• Making antibodies by phage display technology.

  1994cited by this paper
• Humanised monoclonal antibodies for therapeutic applications

  1994cited by this paper
• Section Review: Humanised monoclonal antibodies for therapeutic applications

  1994cited by this paper
• Cancer Research Campaign operation manual for control recommendations for products derived from recombinant DNA technology prepared for investigational administration to patients with cancer in phase I trials.

  1993influential reference
• Radioimmunoguided surgery for colorectal cancer.

  1993cited by this paper
• The effect of circulating antigen and radiolabel stability on the biodistribution of an indium labelled antibody.

  1991cited by this paper
• The Use of In Vitro Immunization, Cloning of Variable Regions, and SCID Mice for the Production of Human Monoclonal Antibodies

  1990cited by this paper
• Mouse/human chimeric monoclonal antibody in man: kinetics and immune response.

  1989cited by this paper
• Reshaping human antibodies: grafting an antilysozyme activity.

  1988cited by this paper
• Repeated antitumour antibody therapy in man with suppression of the host response by cyclosporin A.

  1988cited by this paper
• Remission induction in non-Hodgkin lymphoma with reshaped human monoclonal antibody CAMPATH-1H.

  1988cited by this paper
• Operation manual for control of production, preclinical toxicology and phase I trials of anti-tumour antibodies and drug antibody conjugates. Prepared by a Joint Committee of the: Cancer Research Campaign National Institute for Biological Standards and Control.

  1986cited by this paper
• The use of radionuclides for tumor therapy.

  1986cited by this paper
• Renal handling of proteins in normal and disease states.

  1985cited by this paper

• Carrier systems of radiopharmaceuticals and the application in cancer therapy

  2024cites this paper
• Short FcRn-Binding Peptides Enable Salvage and Transcytosis of scFv Antibody Fragments.

  2022cites this paper
• In vivo Phage Display: A promising selection strategy for the improvement of antibody targeting and drug delivery properties

  2022cites this paper
• Combination radionuclide therapy: A new paradigm.

  2021cites this paper
• Development of bispecific anti-c-Met/PD-1 diabodies for the treatment of solid tumors and the effect of c-Met binding affinity on efficacy

  2021cites this paper
• Radioimmunotherapy in Oncology: Overview of the Last Decade Clinical Trials

  2021cites this paper
• Recent developments in antibody derivatives against colorectal cancer; A review.

  2020cites this paper
• Utilizing Solid Phase Cloning , Surface Display And Epitope Information for Antibody Generation and Characterization

  2017cites this paper
• Antibody engineering of a cytotoxic monoclonal antibody 84 against human embryonic stem cells: Investigating the effects of multivalency on cytotoxicity.

  2017cites this paper
• Chapter 22 – Targeted Radionuclide Therapy

  2016cites this paper
• Significant Therapeutic Efficacy with Combined Radioimmunotherapy and Cetuximab in Preclinical Models of Colorectal Cancer

  2015cites this paper
• The application of monoclonal antibodies in cancer diagnosis

  2014cites this paper
• Production, purification and biological characterization of mono-PEGylated anti-IL-17A antibody fragments.

  2013cites this paper
• General overview of radioimmunotherapy of solid tumors.

  2013cites this paper
• Chapter 22 – Targeted Radionuclide Therapy—Expanded Content

  2012cites this paper
• Recombinant Antibodies as Therapeutic Agents

  2012cites this paper
• One-pot synthesis of an 125I-labeled trifunctional reagent for multiscale imaging with optical and nuclear techniques.

  2011cites this paper
• Phase I Clinical Trial of the 131I-Labeled Anticarcinoembryonic Antigen CIGB-M3 Multivalent Antibody Fragment

  2011cites this paper
• Clinical radioimmunotherapy—the role of radiobiology

  2011cites this paper
• Protein-based tumor molecular imaging probes

  2011cites this paper
• Development of Antibody Fragments for Therapeutic Applications

  2011cites this paper
• Development of an intrabody capable of activating interferon regulatory factor-1 [IRF-1] and identification of IRF-1-binding peptide motifs

  2011cites this paper
• Construction of non-covalent single-chain Fv dimers for hepatocellular carcinoma and their biological functions.

  2010cites this paper
• Modeling the three-dimensional structures of an unbound single-chain variable fragment (scFv) and its hypothetical complex with a Corynespora cassiicola toxin, cassiicolin

  2010cites this paper
• Multivalent antibodies: when design surpasses evolution.

  2010cites this paper
• Design and Characterization of Novel Nanomaterials for Cancer Imaging and Therapy

  2009cites this paper
• Microdistribution of Targeted, Fluorescently Labeled Anti–Carcinoembryonic Antigen Antibody in Metastatic Colorectal Cancer: Implications for Radioimmunotherapy

  2008cites this paper
• Targeted radionuclide therapy.

  2008cites this paper
• Recombinant antibodies as therapeutic agents: pathways for modeling new biodrugs.

  2008cites this paper
• Novel Immunotherapies for EBV-Associated Cancers

  2008cites this paper
• A novel antibody AA98 V(H)/L directed against CD146 efficiently inhibits angiogenesis.

  2007cites this paper
• Predicting response to radioimmunotherapy from the tumor microenvironment of colorectal carcinomas.

  2007cites this paper
• Technology and Production of Murine Monoclonal and Recombinant Antibodies and Antibody Fragments

  2007cites this paper
• Ligand-Targeted Delivery of Therapeutic siRNA

  2006cites this paper
• Therapeutic expression of an anti-death receptor 5 single-chain fixed-variable region prevents tumor growth in mice.

  2006cites this paper
• Characterisation and internalisation of recombinant humanised HMFG-1 antibodies against MUC1

  2005cites this paper
• Engineered antibody fragments and the rise of single domains

  2005cites this paper
• Quantitative evaluation of a monoclonal antibody and its fragment as potential markers for pancreatic beta cell mass.

  2005cites this paper
• Radioimmunotherapy with engineered antibodies

  2004cites this paper
• Anti-carcinoembryonic antigen immunity.

  2003cites this paper
• The crystal structure of an anti-CEA scFv diabody assembled from T84.66 scFvs in V(L)-to-V(H) orientation: implications for diabody flexibility.

  2003cites this paper
• Chapter 23. Recent advances in antibody drug conjugates for cancer therapy

  2003cites this paper
• Engineered antibodies

  2003cites this paper
• Recombinant antibodies for cancer diagnosis and therapy

  2003cites this paper
• Constructs of biotin mimetic peptide with CC49 single-chain Fv designed for tumor pretargeting.

  2003cites this paper
• Ligand-targeted therapeutics in anticancer therapy

  2002cites this paper
• Recombinant antibodies for cancer diagnosis and therapy

  2001cites this paper