Research Topic

Alternative Variable Domains in Therapeutic Antibody Discovery

About this Research Topic

Since the original fusion of mouse splenocytes and P2X cells in the 1970s, monoclonal antibody technology has continued to evolve to address unmet medical needs. While the earliest approved therapeutics derived from mice in a classical IgG format, today, a variety of non-mammalian species are beginning to populate the therapeutic antibody discovery space. Several factors drive this innovation. First, the evolutionary distance of non-mammalian species results in different antibody responses compared to those observed in traditional rodent-based hyperimmunization programs. A wider and more diverse range of paratopes will increase our ability to efficiently target proteins of interest. Secondly, many of these species evolved to express antibodies with unique structural and biochemical characteristics which further contribute to our ability to target a broader epitope space.  


This Research Topic aims to highlight the unique antibodies derived from divergent species and current efforts directed at bringing them to the clinic. For example, at 12-15 kDa, the antigen-binding variable domain (VNAR) of sharks, is half the size of the human Fv and demonstrates better solubility and tissue penetrating ability as a result. Nanobodies derived from dromedaries possess long CDRH3 loops that give their antibodies a unique contoured surface capable of reaching recessed epitopes like catalytic clefts. The cow CDRH3 also adopts a unique configuration in which the ultralong CDR protrudes from the rest of the molecule in a knob/stalk structure. Evolutionary divergence coupled with unique secondary structure characteristics have resulted in increased interest in the use of alternative variable domains in clinical research. Ultimately, the ability to access the antibody repertoires of these species will increase the reach of the pharmaceutical landscape. 


We welcome the submission of articles, covering, but not limited to, the following subtopics:


1. Application of nanobodies as antibody-drug conjugates

2. Advances in the humanization of novel scaffolds

3. Library design and construction for phage or other display technologies

4. Deep sequencing and immune repertoire analysis

5. Strategies in antibody development and optimization (e.g. sequence liabilities, solubility, immunogenicity, etc.)

6. Human or veterinary clinical applications

7. Crystal structures 

Topic Editor Dr. Ching in employed by Ligand Pharmaceuticals. Topic Editor Dr. Smider is the founder of Minotaur Therapeutics. The other Topic Editors declare no competing interests with regards to the Research Topic subject.


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

Since the original fusion of mouse splenocytes and P2X cells in the 1970s, monoclonal antibody technology has continued to evolve to address unmet medical needs. While the earliest approved therapeutics derived from mice in a classical IgG format, today, a variety of non-mammalian species are beginning to populate the therapeutic antibody discovery space. Several factors drive this innovation. First, the evolutionary distance of non-mammalian species results in different antibody responses compared to those observed in traditional rodent-based hyperimmunization programs. A wider and more diverse range of paratopes will increase our ability to efficiently target proteins of interest. Secondly, many of these species evolved to express antibodies with unique structural and biochemical characteristics which further contribute to our ability to target a broader epitope space.  


This Research Topic aims to highlight the unique antibodies derived from divergent species and current efforts directed at bringing them to the clinic. For example, at 12-15 kDa, the antigen-binding variable domain (VNAR) of sharks, is half the size of the human Fv and demonstrates better solubility and tissue penetrating ability as a result. Nanobodies derived from dromedaries possess long CDRH3 loops that give their antibodies a unique contoured surface capable of reaching recessed epitopes like catalytic clefts. The cow CDRH3 also adopts a unique configuration in which the ultralong CDR protrudes from the rest of the molecule in a knob/stalk structure. Evolutionary divergence coupled with unique secondary structure characteristics have resulted in increased interest in the use of alternative variable domains in clinical research. Ultimately, the ability to access the antibody repertoires of these species will increase the reach of the pharmaceutical landscape. 


We welcome the submission of articles, covering, but not limited to, the following subtopics:


1. Application of nanobodies as antibody-drug conjugates

2. Advances in the humanization of novel scaffolds

3. Library design and construction for phage or other display technologies

4. Deep sequencing and immune repertoire analysis

5. Strategies in antibody development and optimization (e.g. sequence liabilities, solubility, immunogenicity, etc.)

6. Human or veterinary clinical applications

7. Crystal structures 

Topic Editor Dr. Ching in employed by Ligand Pharmaceuticals. Topic Editor Dr. Smider is the founder of Minotaur Therapeutics. The other Topic Editors declare no competing interests with regards to the Research Topic subject.


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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Submission Deadlines

30 June 2021 Abstract
30 November 2021 Manuscript

Participating Journals

Manuscripts can be submitted to this Research Topic via the following journals:

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Topic Editors

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Submission Deadlines

30 June 2021 Abstract
30 November 2021 Manuscript

Participating Journals

Manuscripts can be submitted to this Research Topic via the following journals:

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