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Antibodies
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Bispecific Antibodies-Opportunities and Challenges
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Bispecific Antibodies-Opportunities and Challenges

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

Deadline for manuscript submissions: closed (31 May 2018) | Viewed by 49102

Special Issue Editor

Prof. Itai Benhar

E-Mail Website
Guest Editor
The Morris and Manja Leigh Chair in Biophysics and Biotechnology, Vice Dean for Research, the George S. Wise Faculty of Life Sciences, School of Molecular Cell Biology and Biotechnology, Department of Molecular Microbiology and Biotechnology, Green Building room 202, Tel-Aviv University, Ramat Aviv 69978, Israel
Interests: evaluation of novel formats of bispecific antibodies as potential therapeutics; antibodies and antibody-drug combinations for allergy, fibrosis and inflammatory bowel diseases; targeted nanomedicines
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Bispecific antibodies are increasingly becoming instrumental for diagnostic and therapeutic applications. While natural antibodies are monospecific, bispecific antibodies can bind two different epitopes, either on the same or on different antigens. Initially, bispecific antibodies were generated by chemical conjugation of two monoclonal antibodies or by fusion of two antibody-producing hybridomas. Later, a diverse toolkit of antibody engineering approaches enabled the development of recombinant bispecific antibodies of remarkable diversity in structural, functional, and pharmacological properties. Presently, more than 100 different formats for making bispecific antibodies exist, of which about 30 are in clinical development, suggesting they have successfully met developmental criteria. Applications of bispecific antibodies span the entire range of biomedical applications including diagnosis, imaging, prophylaxis and therapy. Bispecific antibodies that artificially recruit effector cells were the first to be developed and to receive FDA or EMA approvals. Later, bispecific antibodies have been developed that retarget effector molecules, cells and genetic vehicles, that enable dual targeting and pretargeting strategies and that delivery through biological barriers, such as the blood–brain barrier.

Recently, it was stated that “after decades of optimization of bispecific formats, screening platforms and manufacturing processes, bispecific antibodies are at last ready to deliver”. 

This Special Issue is aimed to provide an up-to date description of the field, including formats, applications, in particular those unique to bispecific antibodies, expression systems and issues related to development.

Prof. Itai Benhar
Guest Editor

Manuscript Submission Information

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. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short 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 thoroughly refereed through a single-blind 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 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Bispecific antibodies
  • Fragment-based bispecific antibodies
  • IgG and IgG-like bispecific antibodies
  • Unique application of bispecific antibodies
  • Production and developability of bispecific antibodies

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Published Papers (4 papers)

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Research

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16 pages, 2237 KiB  
Article
Relative Contribution of Framework and CDR Regions in Antibody Variable Domains to Multimerisation of Fv- and scFv-Containing Bispecific Antibodies
by Pallavi Bhatta and David P. Humphreys
Antibodies 2018, 7(3), 35; https://doi.org/10.3390/antib7030035 - 31 Aug 2018
Cited by 9 | Viewed by 10320
Abstract
Bispecific antibodies represent an emerging class of antibody drugs that are commonly generated by fusion of Fv or scFv antigen binding domains to IgG or Fab scaffolds. Fv- or scFv-mediated multimerisation of bispecific antibodies via promiscuous vH-vL pairing can result in sub-optimal monomer [...] Read more.
Bispecific antibodies represent an emerging class of antibody drugs that are commonly generated by fusion of Fv or scFv antigen binding domains to IgG or Fab scaffolds. Fv- or scFv-mediated multimerisation of bispecific antibodies via promiscuous vH-vL pairing can result in sub-optimal monomer levels during expression, and hence, undesirable therapeutic protein yields. We investigate the contribution of disulphide stabilised Fv and scFv to Fab-Fv and Fab-scFv multimerisation. We show that monomer levels of isolated Fv/scFv cannot always be used to predict monomer levels of Fab-linked Fv/scFv, and that Fab-scFv monomer levels are greater than the equivalent Fab-Fv. Through grafting bispecifics with framework/CDR-‘swapped’ Fv and scFv, we show that monomer levels of disulphide stabilised Fab-Fv and Fab-scFv can be improved by Fv framework ‘swapping’. The Fab-Fv and Fab-scFv can be considered representative of the significant number of bispecific antibody formats containing appended Fv/scFv, as we also used Fv framework ‘swapping’ to increase the monomer level of an IgG-scFv bispecific antibody. This research may, therefore, be useful for maximising the monomeric yield of numerous pharmaceutically-relevant bispecific formats in pre-clinical development. Full article
(This article belongs to the Special Issue Bispecific Antibodies-Opportunities and Challenges)
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13 pages, 4772 KiB  
Article
Tuning Relative Polypeptide Expression to Optimize Assembly, Yield and Downstream Processing of Bispecific Antibodies
by Giovanni Magistrelli, Guillemette Pontini, Yves Poitevin, Pauline Malinge, Jérémie Bourguignon, Florence Gauye, Elise Fleury, Nicolas Plèche, Lydia Galissaires and Nicolas Fischer
Antibodies 2018, 7(3), 29; https://doi.org/10.3390/antib7030029 - 10 Aug 2018
Cited by 7 | Viewed by 6292
Abstract
Bispecific antibodies (bsAbs) are often composed of several polypeptide chains that have to be expressed adequately to enable optimal assembly and yield of the bsAb. κλ bodies are a bispecific format with a native IgG structure, composed of two different light chains that [...] Read more.
Bispecific antibodies (bsAbs) are often composed of several polypeptide chains that have to be expressed adequately to enable optimal assembly and yield of the bsAb. κλ bodies are a bispecific format with a native IgG structure, composed of two different light chains that pair with a common heavy chain. Introduction of non-optimal codons into the sequence of a particular polypeptide is an effective strategy for down modulating its expression. Here we applied this strategy but restricted the modification of the codon content to the constant domain of one light chain. This approach facilitates parallel optimization of several bsAbs by using the same modified constant domains. Partial sequence de-optimization reduced expression of the targeted polypeptide. Stable cell pools could be isolated displaying increased bispecific antibody titers as well as changes in the abundance of undesired by-products that require elimination during downstream processing. Thus, modulating the relative expression of polypeptides can have a significant impact on bsAb titer and product related impurities; which are important factors for large scale manufacturing for clinical supply. Full article
(This article belongs to the Special Issue Bispecific Antibodies-Opportunities and Challenges)
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28 pages, 4399 KiB  
Article
Design Principles for Bispecific IgGs, Opportunities and Pitfalls of Artificial Disulfide Bonds
by Lilach Vaks, Dana Litvak-Greenfeld, Stav Dror, LeeRon Shefet-Carasso, Galia Matatov, Limor Nahary, Shiran Shapira, Rahely Hakim, Iris Alroy and Itai Benhar
Antibodies 2018, 7(3), 27; https://doi.org/10.3390/antib7030027 - 28 Jul 2018
Cited by 11 | Viewed by 13514
Abstract
Bispecific antibodies (bsAbs) are antibodies with two binding sites directed at different antigens, enabling therapeutic strategies not achievable with conventional monoclonal antibodies (mAbs). Since bispecific antibodies are regarded as promising therapeutic agents, many different bispecific design modalities have been evaluated, but as many [...] Read more.
Bispecific antibodies (bsAbs) are antibodies with two binding sites directed at different antigens, enabling therapeutic strategies not achievable with conventional monoclonal antibodies (mAbs). Since bispecific antibodies are regarded as promising therapeutic agents, many different bispecific design modalities have been evaluated, but as many of them are small recombinant fragments, their utility could be limited. For some therapeutic applications, full-size IgGs may be the optimal format. Two challenges should be met to make bispecific IgGs; one is that each heavy chain will only pair with the heavy chain of the second specificity and that homodimerization be prevented. The second is that each heavy chain will only pair with the light chain of its own specificity and not with the light chain of the second specificity. The first solution to the first criterion (knobs into holes, KIH) was presented in 1996 by Paul Carter’s group from Genentech. Additional solutions were presented later on. However, until recently, out of >120 published bsAb formats, only a handful of solutions for the second criterion that make it possible to produce a bispecific IgG by a single expressing cell were suggested. We present a solution for the second challenge—correct pairing of heavy and light chains of bispecific IgGs; an engineered (artificial) disulfide bond between the antibodies’ variable domains that asymmetrically replaces the natural disulfide bond between CH1 and CL. We name antibodies produced according to this design “BIClonals”. Bispecific IgGs where the artificial disulfide bond is placed in the CH1-CL interface are also presented. Briefly, we found that an artificial disulfide bond between VH position 44 to VL position 100 provides for effective and correct H–L chain pairing while also preventing the formation of wrong H–L chain pairs. When the artificial disulfide bond links the CH1 with the CL domain, effective H–L chain pairing also occurs, but in some cases, wrong H–L pairing is not totally prevented. We conclude that H–L chain pairing seems to be driven by VH–VL interfacial interactions that differ between different antibodies, hence, there is no single optimal solution for effective and precise assembly of bispecific IgGs, making it necessary to carefully evaluate the optimal solution for each new antibody. Full article
(This article belongs to the Special Issue Bispecific Antibodies-Opportunities and Challenges)
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Review

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10 pages, 1101 KiB  
Review
Engineering IgG-Like Bispecific Antibodies—An Overview
by Simon Krah, Harald Kolmar, Stefan Becker and Stefan Zielonka
Antibodies 2018, 7(3), 28; https://doi.org/10.3390/antib7030028 - 1 Aug 2018
Cited by 41 | Viewed by 17838
Abstract
Monoclonal antibody therapeutics have proven to be successful treatment options for patients in various indications. Particularly in oncology, therapeutic concepts involving antibodies often rely on the so-called effector functions, such as antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC), which are [...] Read more.
Monoclonal antibody therapeutics have proven to be successful treatment options for patients in various indications. Particularly in oncology, therapeutic concepts involving antibodies often rely on the so-called effector functions, such as antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC), which are programed in the antibody Fc region. However, Fc-mediated effector mechanisms often seem to be insufficient in properly activating the immune system to act against tumor cells. Furthermore, long term treatments can lead to resistance against the applied drug, which is monospecific by nature. There is promise in using specific antibodies to overcome such issues due to their capability of recruiting and activating T-cells directly at the tumor site, for instance. During the last decade, two of these entities, which are referred to as Blinatumomab and Catumaxomab, have been approved to treat patients with acute lymphoblastic leukemia and malignant ascites. In addition, Emicizumab, which is a bispecific antibody targeting clotting factors IXa and X, was recently granted market approval by the FDA in 2017 for the treatment of hemophilia A. However, the generation of these next generation therapeutics is challenging and requires tremendous engineering efforts as two distinct paratopes need to be combined from two different heavy and light chains. This mini review summarizes technologies, which enable the generation of antibodies with dual specificities. Full article
(This article belongs to the Special Issue Bispecific Antibodies-Opportunities and Challenges)
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