Special Issue "Bispecific Antibodies for Dual Targeting Strategies"

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A special issue of Antibodies (ISSN 2073-4468).

Deadline for manuscript submissions: closed (28 February 2013)

Special Issue Editor

Guest Editor
Prof. Dr. Roland Kontermann

Institut für Zellbiologie und Immunologie, Universität Stuttgart, Allmandring 31, D-70569 Stuttgart, Germany
Website | E-Mail
Interests: bifunctional antibody fusion proteins; half-life extension strategies; targeted nanoparticulate drug delivery systems

Special Issue Information

Dear Colleagues,

Bispecific antibodies are emerging as novel approach for dual targeting strategies combining two different antigen-binding sites within one molecules. Bispecific antibodies allow to improve binding, selectivity and efficacy, e.g. by simultaneously inhibiting two receptors or cytokines. A multitude of bispecific antibody formats have been developed in the recent years and novel applications have been established, including the dual retargeting of toxins, cytokines and growth factors with bispecific antibody fusion proteins but also dual retargeting of effector cells of the immune system with trispecific antibodies. Furthermore, dual targeting is applied to nanoparticles for delivery of drugs to target cells. Main indications include tumor therapy and the treatment of inflammatory diseases, but new areas for application of dual targeting strategies are also emerging, e.g. in diagnosis and imaging. Recent studies have already shown that bispecific antibodies show similar or even improved efficacy compared with combination therapy with two antibodies, thus offer an alternative to the parallel development, production and approval of two monoclonal antibodies.

This special issue of Antibodies addresses the growing interest in dual targeting strategies using bispecific antibodies and I kindly invite you to submit your novel results to this special issue. Welcome are manuscripts describing the application of bispecific antibodies for dual targeting strategies using in vitro and in vivo studies as well as manuscript dealing with novel bispecific antibody formats and fusion proteins suitable for dual targeting strategies.

Prof. Dr. Roland E. Kontermann
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibodies is an international peer-reviewed Open Access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 300 CHF (Swiss Francs). English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.

Keywords

  • bispecific antibodies for dual targeting of tumor cells
  • bispecific antibodies for dual neutralization of cytokines and growth factors
  • bispecific antibodies for dual targeting for receptor activation
  • bispecific antibodies for dual retargeting of cytokines and growth factors
  • bispecific antibodies for dual retargeting of immune effector cells
  • bispecific antibodies for dual retargeting of toxins
  • antibodies for dual retargeting of nanoparticles and liposomes
  • new bispecific antibody formats
  • bispecific antibodies for tumor therapy
  • bispecific antibodies for therapy of inflammatory diseases
  • bispecific antibodies for therapy of infectious diseases
  • bispecific antibodies for imaging and diagnosis
  • bispecific antibodies for half-life extension

Published Papers (7 papers)

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Research

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Open AccessArticle Immunotherapy of B-Cell Lymphoma with an Engineered Bispecific Antibody Targeting CD19 and CD5
Antibodies 2013, 2(2), 338-352; doi:10.3390/antib2020338
Received: 26 March 2013 / Revised: 22 April 2013 / Accepted: 22 April 2013 / Published: 14 May 2013
Cited by 1 | PDF Full-text (588 KB) | HTML Full-text | XML Full-text
Abstract
Using genetic engineering a humanized Fab fragment with specificity for CD19 was fused to a disulfide-stabilized single-chain antibody (dsFv) recognizing CD5. This format should show reduced immunogenicity and improved tissue penetration. The specificity of bsAb FabCD19xdsFvCD5 binding to target cells was verified by
[...] Read more.
Using genetic engineering a humanized Fab fragment with specificity for CD19 was fused to a disulfide-stabilized single-chain antibody (dsFv) recognizing CD5. This format should show reduced immunogenicity and improved tissue penetration. The specificity of bsAb FabCD19xdsFvCD5 binding to target cells was verified by flow cytometry on B and T lymphoma cell lines. Binding affinities of both arms were compared with the bivalent parental antibodies against CD19 and CD5 by binding competition assay. Redirected lysis of B lymphoma cells by preactivated PBMC from healthy donors was demonstrated in a chromium-release assay. A clear dose-response relationship could be established in the range from 1 ng/mL to 10 mg/mL bsAb. To evaluate the in vivo efficacy of bsAb FabCD19xdsFvCD5, NOD/SCID mice were intravenously injected with luciferase transfected Raji lymphoma cells together with pre-activated PBMC. Mice received five injections of therapeutic bsAb or control antibodies. While in the control groups all mice died within 40 to 50 days, 40% of bsAb treated animals survived longer than 60 days. Full article
(This article belongs to the Special Issue Bispecific Antibodies for Dual Targeting Strategies)
Open AccessArticle Dual Targeting of Tumor Cells with Bispecific Single-Chain Fv-Immunoliposomes
Antibodies 2012, 1(2), 199-214; doi:10.3390/antib1020199
Received: 8 May 2012 / Revised: 9 July 2012 / Accepted: 13 July 2012 / Published: 25 July 2012
Cited by 11 | PDF Full-text (799 KB) | HTML Full-text | XML Full-text
Abstract
Antibody fragments, especially single-chain Fv fragments, have been established for the generation of immunoliposomes for targeted drug delivery in cancer therapy and other applications. Bispecific immunoliposomes should be useful for dual targeting addressing inter- and intratumoral heterogeneity of tumor antigen expression. Here, we
[...] Read more.
Antibody fragments, especially single-chain Fv fragments, have been established for the generation of immunoliposomes for targeted drug delivery in cancer therapy and other applications. Bispecific immunoliposomes should be useful for dual targeting addressing inter- and intratumoral heterogeneity of tumor antigen expression. Here, we established a protocol to generate dual-targeted immunoliposomes using genetically engineered scFv molecules recognizing two different tumor-associated antigens, EGFR and CEA (CEACAM5), applying a step-wise insertion of antibody-coupled micelles into preformed PEGylated liposomes. The dual-targeted immunoliposomes retained binding activity for both antigens and combined the selectivity of both antibodies within one liposome. Thus, these dual-targeted immunoliposomes should be suitable to deliver therapeutic payloads to tumor cells expressing EGFR or CEA, or both antigens. Full article
(This article belongs to the Special Issue Bispecific Antibodies for Dual Targeting Strategies)
Figures

Open AccessArticle A Cassette Vector System for the Rapid Cloning and Production of Bispecific Tetravalent Antibodies
Antibodies 2012, 1(1), 19-38; doi:10.3390/antib1010019
Received: 1 March 2012 / Revised: 28 March 2012 / Accepted: 30 March 2012 / Published: 11 April 2012
Cited by 2 | PDF Full-text (800 KB) | HTML Full-text | XML Full-text
Abstract
Bivalent single chain (sc)Fv-Fc antibodies have been used for years as recombinant alternatives of natural immunoglobulins. We have extended this approach to the scFv-Fc-scFv antibody format to obtain tetravalent antigen binding and the possibility to generate bispecific antibodies. We developed a mammalian expression
[...] Read more.
Bivalent single chain (sc)Fv-Fc antibodies have been used for years as recombinant alternatives of natural immunoglobulins. We have extended this approach to the scFv-Fc-scFv antibody format to obtain tetravalent antigen binding and the possibility to generate bispecific antibodies. We developed a mammalian expression vector system to construct tetravalent scFv-Fc-scFv antibodies with two NcoI+NotI compatible cloning sites flanking the Fc gene fragment. We demonstrated direct cloning from single chain antibody gene libraries and tested various scFv combinations. Transient production of scFv-Fc-scFv antibodies in human embryonic kidney (HEK) 293T cells achieved volumetric yields of up to 10 mg/L. However, expression levels were strongly dependent on the carboxyterminal scFv and the scFv combination. All scFv-Fc-scFv antibodies exclusively formed disulfide-linked homodimers. Antigen binding studies revealed dual specificity for all scFv-Fc-scFv employing different scFv fragments. Comparison of C-reactive protein (CRP) specific monovalent scFv LA13-IIE3, bivalent scFv-Fc and Fc-scFv LA13-IIE3, and tetravalent scFv-Fc-scFv (scFv LA13-IIE3 in combination with scFvs LA13-IIE3, TOB4-B11, or TOB5-D4) revealed an up to 500-fold increased antigen binding. This novel scFv-Fc-scFv antibody expression system allows simple and fast testing of various scFv combinations. Full article
(This article belongs to the Special Issue Bispecific Antibodies for Dual Targeting Strategies)

Review

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Open AccessReview In Vivo Secretion of Bispecific Antibodies Recruiting Lymphocytic Effector Cells
Antibodies 2013, 2(3), 415-425; doi:10.3390/antib2030415
Received: 13 March 2013 / Revised: 6 June 2013 / Accepted: 19 June 2013 / Published: 27 June 2013
PDF Full-text (599 KB) | HTML Full-text | XML Full-text
Abstract
Engineered Fc-lacking bispecific antibodies have shown an exceptionally high potency for recruiting lymphocyte effector cells and enhancing antitumor activity, which is under evaluation in several clinical trials. However, current treatment regimens raise some issues that should be considered, such as the high cost
[...] Read more.
Engineered Fc-lacking bispecific antibodies have shown an exceptionally high potency for recruiting lymphocyte effector cells and enhancing antitumor activity, which is under evaluation in several clinical trials. However, current treatment regimens raise some issues that should be considered, such as the high cost of clinical-grade bispecific antibodies and the achievement of sustained therapeutic plasma levels. The use of gene transfer methods may circumvent problems related to large-scale production and purification, and result in sustained therapeutic plasma concentrations of the Fc-lacking bispecific antibodies. In fact, terminally differentiated cells and non-terminally differentiated cells can be genetically modified to secrete functionally active bispecific antibodies exerting clear anti-tumor effects. This review highlights the relevance of different promising strategies for in vivo delivery of therapeutic bispecific antibodies. Full article
(This article belongs to the Special Issue Bispecific Antibodies for Dual Targeting Strategies)
Open AccessReview The Development of Bispecific Hexavalent Antibodies as a Novel Class of DOCK-AND-LOCKTM (DNLTM) Complexes
Antibodies 2013, 2(2), 353-370; doi:10.3390/antib2020353
Received: 1 March 2013 / Revised: 9 May 2013 / Accepted: 13 May 2013 / Published: 23 May 2013
Cited by 3 | PDF Full-text (532 KB) | HTML Full-text | XML Full-text
Abstract
The DOCK-AND-LOCKTM (DNLTM) method provides a modular approach to develop multivalent, multifunctional complexes of defined structures, of which bispecific hexavalent antibodies (bsHexAbs) are prominent examples with potential applications in targeted therapy for malignant, autoimmune, and infectious diseases. Currently, bsHexAbs are
[...] Read more.
The DOCK-AND-LOCKTM (DNLTM) method provides a modular approach to develop multivalent, multifunctional complexes of defined structures, of which bispecific hexavalent antibodies (bsHexAbs) are prominent examples with potential applications in targeted therapy for malignant, autoimmune, and infectious diseases. Currently, bsHexAbs are constructed by derivatizing a divalent IgG, at the carboxyl termini of either the heavy chain (the CH3-format) or the light chain (the Ck-format), to contain two stabilized dimers of Fab having a different specificity from the IgG. In this review, we briefly outline the features of the DNLTM method and describe key aspects of bsHexAbs examined with diverse preclinical studies, which include binding affinity to target cells, induction of signaling pathways, effector functions, serum stability, pharmacokinetics, and antitumor activity in human tumor xenograft models. Our findings favor the selection of the CK- over the CH3-format for further exploration of bsHexAbs in clinical trials. Full article
(This article belongs to the Special Issue Bispecific Antibodies for Dual Targeting Strategies)
Open AccessReview Cancer Immunotherapy by Retargeting of Immune Effector Cells via Recombinant Bispecific Antibody Constructs
Antibodies 2012, 1(2), 172-198; doi:10.3390/antib1020172
Received: 24 May 2012 / Revised: 27 June 2012 / Accepted: 10 July 2012 / Published: 18 July 2012
Cited by 12 | PDF Full-text (623 KB) | HTML Full-text | XML Full-text
Abstract
Immunotherapy has emerged as an alternative strategy to treat malignancies in addition to conventional radio- and chemotherapy. There has been a plethora of evidence that the immune system is able to control tumor outgrowth and a number of strategies have been put forward
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Immunotherapy has emerged as an alternative strategy to treat malignancies in addition to conventional radio- and chemotherapy. There has been a plethora of evidence that the immune system is able to control tumor outgrowth and a number of strategies have been put forward to utilize this ability for immunotherapy. However, some of these strategies have not been very efficient and their success has been limited by tumor evasion mechanisms. A promising approach to engage effector cells of the immune system overcoming some of the escape mechanisms has been introduced more than two decades ago. This approach is based on bispecific antibodies. Here we summarize the evolution of bispecific antibodies, their improvement, remaining obstacles and some controversial reports. Full article
(This article belongs to the Special Issue Bispecific Antibodies for Dual Targeting Strategies)
Open AccessReview Dual-Targeting for the Elimination of Cancer Cells with Increased Selectivity
Antibodies 2012, 1(1), 2-18; doi:10.3390/antib1010002
Received: 28 February 2012 / Revised: 16 March 2012 / Accepted: 30 March 2012 / Published: 10 April 2012
Cited by 8 | PDF Full-text (665 KB) | HTML Full-text | XML Full-text
Abstract
Here we review recombinant proteins with a capability for dual-targeting. These molecules address two different antigens on the same tumor cell and therefore are called “dual-targeting agents”. By virtue of binding a chosen pair of antigens on the malignant cell, preferential binding to
[...] Read more.
Here we review recombinant proteins with a capability for dual-targeting. These molecules address two different antigens on the same tumor cell and therefore are called “dual-targeting agents”. By virtue of binding a chosen pair of antigens on the malignant cell, preferential binding to antigen double-positive over single-positive cells can be achieved when both are present in the same environment. Therapeutic effects of such agents are based on different modes of action: (1) They can act as pro-apoptotic agents or by inhibiting pro-survival signals; (2) The dual recognition moiety can be fused to effector-domains, such as bacterial toxins or other drugs, leading to the generation of bispecific antibody-drug conjugates (ADCs); (3) Dual-targeting agents can further be used to redirect an effector-cell to the tumor. A new generation of scFv-derived fusion proteins are the tandem single chain triplebodies (sctbs), which carry two scFv binding sites for antigens on the tumor cell plus a third, specific for a trigger molecule on an effector cell. The ability of preferential or selective targeting of antigen double-positive over single-positive cells opens attractive new perspectives for the use of dual-targeting agents in cancer therapy, and possibly also for the treatment of certain inflammatory and autoimmune disorders. Full article
(This article belongs to the Special Issue Bispecific Antibodies for Dual Targeting Strategies)

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