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Article ; Online: Humanization of Camelid Single-Domain Antibodies.

Sulea, Traian

Methods in molecular biology (Clifton, N.J.)

2022 Volume 2446, Page(s) 299–312

Abstract: Humanization of therapeutic antibodies derived from animal immunizations is often required to minimize immunogenicity risks in humans, which can cause potentially harmful and serious side effects and reduce antibody efficacy. Humanization is typically ... ...

Abstract	Humanization of therapeutic antibodies derived from animal immunizations is often required to minimize immunogenicity risks in humans, which can cause potentially harmful and serious side effects and reduce antibody efficacy. Humanization is typically applied to conventional monoclonal antibodies derived in rodents as well as single-domain antibodies isolated from camelids and sharks (VHHs and VNARs). A streamlined protocol is described here for sequence humanization of camelid VHHs, which represent a promising biotherapeutic format with many desirable attributes. From human framework selection and complementarity-determining region grafting strategies to empirical scoring for prioritization of back-mutations, step-by-step instructions, and templates are provided along with bioinformatics resources to assist each step of the humanization process. Alternative approaches, warnings, and caveats are also presented.
MeSH term(s)	Animals ; Antibodies, Monoclonal, Humanized ; Camelus ; Complementarity Determining Regions/genetics ; Models, Molecular ; Protein Engineering/methods ; Single-Domain Antibodies/genetics
Chemical Substances	Antibodies, Monoclonal, Humanized ; Complementarity Determining Regions ; Single-Domain Antibodies
Language	English
Publishing date	2022-02-14
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-2075-5_14
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Article: Editorial: Progress and challenges in computational structure-based design and development of biologic drugs.

Sulea, Traian / Kumar, Sandeep / Kuroda, Daisuke

Frontiers in molecular biosciences

2024 Volume 11, Page(s) 1360267

Language	English
Publishing date	2024-02-07
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2024.1360267
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Article ; Online: Comparative Performance of High-Throughput Methods for Protein p

Wei, Wanlei / Hogues, Hervé / Sulea, Traian

Journal of chemical information and modeling

2023 Volume 63, Issue 16, Page(s) 5169–5181

Abstract: The medically relevant field of protein-based therapeutics has triggered a demand for protein engineering in different pH environments of biological relevance. ...

Abstract	The medically relevant field of protein-based therapeutics has triggered a demand for protein engineering in different pH environments of biological relevance.
MeSH term(s)	Algorithms ; Amino Acids ; Hydrogen-Ion Concentration ; Proteins/chemistry
Chemical Substances	Amino Acids ; Proteins
Language	English
Publishing date	2023-08-07
Publishing country	United States
Document type	Comparative Study ; Journal Article
ZDB-ID	190019-5
ISSN	1549-960X ; 0095-2338
ISSN (online)	1549-960X
ISSN	0095-2338
DOI	10.1021/acs.jcim.3c00165
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Article ; Online: Enhanced antibody-antigen structure prediction from molecular docking using AlphaFold2.

Gaudreault, Francis / Corbeil, Christopher R / Sulea, Traian

Scientific reports

2023 Volume 13, Issue 1, Page(s) 15107

Abstract: Predicting the structure of antibody-antigen complexes has tremendous value in biomedical research but unfortunately suffers from a poor performance in real-life applications. AlphaFold2 (AF2) has provided renewed hope for improvements in the field of ... ...

Abstract	Predicting the structure of antibody-antigen complexes has tremendous value in biomedical research but unfortunately suffers from a poor performance in real-life applications. AlphaFold2 (AF2) has provided renewed hope for improvements in the field of protein-protein docking but has shown limited success against antibody-antigen complexes due to the lack of co-evolutionary constraints. In this study, we used physics-based protein docking methods for building decoy sets consisting of low-energy docking solutions that were either geometrically close to the native structure (positives) or not (negatives). The docking models were then fed into AF2 to assess their confidence with a novel composite score based on normalized pLDDT and pTMscore metrics after AF2 structural refinement. We show benefits of the AF2 composite score for rescoring docking poses both in terms of (1) classification of positives/negatives and of (2) success rates with particular emphasis on early enrichment. Docking models of at least medium quality present in the decoy set, but not necessarily highly ranked by docking methods, benefitted most from AF2 rescoring by experiencing large advances towards the top of the reranked list of models. These improvements, obtained without any calibration or novel methodologies, led to a notable level of performance in antibody-antigen unbound docking that was never achieved previously.
MeSH term(s)	Molecular Docking Simulation ; Furylfuramide ; Antigen-Antibody Complex ; Benchmarking ; Biological Evolution
Chemical Substances	Furylfuramide (054NR2135Y) ; Antigen-Antibody Complex
Language	English
Publishing date	2023-09-13
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-42090-5
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Article ; Online: Optimizing Antibody-Antigen Binding Affinities with the ADAPT Platform.

Sulea, Traian / Deprez, Christophe / Corbeil, Christopher R / Purisima, Enrico O

Methods in molecular biology (Clifton, N.J.)

2022 Volume 2552, Page(s) 361–374

Abstract: The ADAPT (Assisted Design of Antibody and Protein Therapeutics) platform guides the selection of mutants that improve/modulate the affinity of antibodies and other biologics. Predicted affinities are based on a consensus z-score from three scoring ... ...

Abstract	The ADAPT (Assisted Design of Antibody and Protein Therapeutics) platform guides the selection of mutants that improve/modulate the affinity of antibodies and other biologics. Predicted affinities are based on a consensus z-score from three scoring functions. Computational predictions are interleaved with experimental validation, significantly enhancing the robustness of the design and selection of mutants. A key step is an initial exhaustive virtual single-mutant scan that identifies hot spots and the mutations predicted to improve affinity. A small number of proposed single mutants are then produced and assayed. Only the validated single mutants (i.e., having improved affinity) are used to design double and higher-order mutants in subsequent rounds of design, avoiding the combinatorial explosion that arises from random mutagenesis. Typically, with a total of about 30-50 designed single, double, and triple mutants, affinity improvements of 10- to 100-fold are obtained.
MeSH term(s)	Antibody Affinity ; Mutagenesis ; Antibodies ; Mutation
Chemical Substances	Antibodies
Language	English
Publishing date	2022-11-13
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-2609-2_20
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Article: Solvated interaction energy: from small-molecule to antibody drug design.

Purisima, Enrico O / Corbeil, Christopher R / Gaudreault, Francis / Wei, Wanlei / Deprez, Christophe / Sulea, Traian

Frontiers in molecular biosciences

2023 Volume 10, Page(s) 1210576

Abstract: Scoring functions are ubiquitous in structure-based drug design as an aid to predicting binding modes and estimating binding affinities. Ideally, a scoring function should be broadly applicable, obviating the need to recalibrate and refit its parameters ... ...

Abstract	Scoring functions are ubiquitous in structure-based drug design as an aid to predicting binding modes and estimating binding affinities. Ideally, a scoring function should be broadly applicable, obviating the need to recalibrate and refit its parameters for every new target and class of ligands. Traditionally, drugs have been small molecules, but in recent years biologics, particularly antibodies, have become an increasingly important if not dominant class of therapeutics. This makes the goal of having a transferable scoring function, i.e., one that spans the range of small-molecule to protein ligands, even more challenging. One such broadly applicable scoring function is the Solvated Interaction Energy (SIE), which has been developed and applied in our lab for the last 15 years, leading to several important applications. This physics-based method arose from efforts to understand the physics governing binding events, with particular care given to the role played by solvation. SIE has been used by us and many independent labs worldwide for virtual screening and discovery of novel small-molecule binders or optimization of known drugs. Moreover, without any retraining, it is found to be transferrable to predictions of antibody-antigen relative binding affinities and as accurate as functions trained on protein-protein binding affinities. SIE has been incorporated in conjunction with other scoring functions into ADAPT (Assisted Design of Antibody and Protein Therapeutics), our platform for affinity modulation of antibodies. Application of ADAPT resulted in the optimization of several antibodies with 10-to-100-fold improvements in binding affinity. Further applications included broadening the specificity of a single-domain antibody to be cross-reactive with virus variants of both SARS-CoV-1 and SARS-CoV-2, and the design of safer antibodies by engineering of a pH switch to make them more selective towards acidic tumors while sparing normal tissues at physiological pH.
Language	English
Publishing date	2023-06-07
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2023.1210576
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Article ; Online: Coevolved Canonical Loops Conformations of Single-Domain Antibodies: A Tale of Three Pockets Playing Musical Chairs.

Gaudreault, Francis / Corbeil, Christopher R / Purisima, Enrico O / Sulea, Traian

Frontiers in immunology

2022 Volume 13, Page(s) 884132

Abstract: Single-domain antibodies (sdAbs) are a promising class of biotherapeutics with unique structural traits within their paratope region. The distribution of canonical conformations explored by their complementarity determining region (CDR) loops differs to ... ...

Abstract	Single-domain antibodies (sdAbs) are a promising class of biotherapeutics with unique structural traits within their paratope region. The distribution of canonical conformations explored by their complementarity determining region (CDR) loops differs to some extent from conventional two-chain Fv fragments of monoclonal antibodies (mAbs). In this study, we explored in detail the canonical structures of sdAb CDR-H1 and CDR-H2 loops and compared those with mAbs from the IGHV3 and IGHV1 gene families. We surveyed the antibody structures catalogued in SAbDab and clustered the CDR canonical loops in Cartesian space. While most of the sdAb clusters were sub-populations of previously defined canonical Fv conformations of CDR-H1 and CDR-H2, our stricter clustering approach defined narrower clusters in sequence-space. Meticulous visual inspection of sub-populations allowed a clearer understanding of sequence-structure relationships. The packing densities within structural pockets contacted by CDR-H1 and CDR-H2 canonical conformations were analyzed on the premise that these pockets cannot be left vacant as they would leave exposed supportive hydrophobic residues. The fine resolution of the canonical clusters defined here revealed unique signatures within these pockets, including distinct structural complementarities between CDR-H1 and CDR-H2 canonical clusters, which could not be perceived with the previous coarser clusters. We highlight examples where a single residue change in CDR-H1 sequence is sufficient to induce a dramatic population shift in CDR-H2 conformation. This suggests that preferences in combining CDR-H1 and CDR-H2 emerged naturally during antibody evolution, leading to preferred sets of conserved amino acids at key positions in the framework as well as within the CDR loops. We outline a game of musical chairs that is necessary to maintain the integrity of the antibody structures that arose during evolution. Our study also provides refined CDR-H1 and CDR-H2 structural templates for sdAb homology modeling that could be leveraged for improved antibody design.
MeSH term(s)	Antibodies, Monoclonal ; Complementarity Determining Regions/chemistry ; Models, Molecular ; Protein Conformation ; Single-Domain Antibodies
Chemical Substances	Antibodies, Monoclonal ; Complementarity Determining Regions ; Single-Domain Antibodies
Language	English
Publishing date	2022-06-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.884132
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Article ; Online: Solvated interaction energy

Enrico O. Purisima / Christopher R. Corbeil / Francis Gaudreault / Wanlei Wei / Christophe Deprez / Traian Sulea

Frontiers in Molecular Biosciences, Vol

from small-molecule to antibody drug design

2023 Volume 10

Abstract	Scoring functions are ubiquitous in structure-based drug design as an aid to predicting binding modes and estimating binding affinities. Ideally, a scoring function should be broadly applicable, obviating the need to recalibrate and refit its parameters for every new target and class of ligands. Traditionally, drugs have been small molecules, but in recent years biologics, particularly antibodies, have become an increasingly important if not dominant class of therapeutics. This makes the goal of having a transferable scoring function, i.e., one that spans the range of small-molecule to protein ligands, even more challenging. One such broadly applicable scoring function is the Solvated Interaction Energy (SIE), which has been developed and applied in our lab for the last 15 years, leading to several important applications. This physics-based method arose from efforts to understand the physics governing binding events, with particular care given to the role played by solvation. SIE has been used by us and many independent labs worldwide for virtual screening and discovery of novel small-molecule binders or optimization of known drugs. Moreover, without any retraining, it is found to be transferrable to predictions of antibody-antigen relative binding affinities and as accurate as functions trained on protein-protein binding affinities. SIE has been incorporated in conjunction with other scoring functions into ADAPT (Assisted Design of Antibody and Protein Therapeutics), our platform for affinity modulation of antibodies. Application of ADAPT resulted in the optimization of several antibodies with 10-to-100-fold improvements in binding affinity. Further applications included broadening the specificity of a single-domain antibody to be cross-reactive with virus variants of both SARS-CoV-1 and SARS-CoV-2, and the design of safer antibodies by engineering of a pH switch to make them more selective towards acidic tumors while sparing normal tissues at physiological pH.
Keywords	binding affinity ; solvation ; protein-ligand interaction ; scoring function ; antibody affinity maturation ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
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Article ; Online: Antibody mutations favoring pH-dependent binding in solid tumor microenvironments: Insights from large-scale structure-based calculations.

Wei, Wanlei / Corbeil, Christopher R / Gaudreault, Francis / Deprez, Christophe / Purisima, Enrico O / Sulea, Traian

Proteins

2022 Volume 90, Issue 8, Page(s) 1538–1546

Abstract: Antibody-based therapeutics for treatment of various tumors have grown rapidly in recent years. Unfortunately, safety issues, attributed to off-tumor effects and cytotoxicity, are still a significant concern with the standard of care. Improvements to ... ...

Abstract	Antibody-based therapeutics for treatment of various tumors have grown rapidly in recent years. Unfortunately, safety issues, attributed to off-tumor effects and cytotoxicity, are still a significant concern with the standard of care. Improvements to ensure targeted delivery of antitumor pharmaceuticals are desperately needed. We previously demonstrated that incorporating histidyl pH-switches in an anti-HER2 antibody induced selective antigen binding under acidic pH conditions (MAbs 2020;12:1682866). This led to an improved safety profile due to preferential targeting of the oncoprotein in the acidic solid tumor microenvironment. Following this success, we expanded this approach to a set of over 400 antibody structures complexed with over 100 different human oncoproteins, associated with solid tumors. Calculations suggested that mutations to His of certain residue types, namely Trp, Arg, and Tyr, could be significantly more successful for inducing pH-dependent binding under acidic conditions. Furthermore, 10 positions within the complementarity-determining region were also predicted to exhibit greater successes. Combined, these two accessible metrics could serve as the basis for a sequence-based engineering of pH-selective binding. This approach could be applied to most anticancer antibodies, which lack detailed structural characterization.
MeSH term(s)	Antibodies, Monoclonal/genetics ; Humans ; Hydrogen-Ion Concentration ; Mutation ; Tumor Microenvironment
Chemical Substances	Antibodies, Monoclonal
Language	English
Publishing date	2022-04-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	806683-8
ISSN	1097-0134 ; 0887-3585
ISSN (online)	1097-0134
ISSN	0887-3585
DOI	10.1002/prot.26340
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Article: Exploring rigid-backbone protein docking in biologics discovery: a test using the DARPin scaffold.

Gaudreault, Francis / Baardsnes, Jason / Martynova, Yuliya / Dachon, Aurore / Hogues, Hervé / Corbeil, Christopher R / Purisima, Enrico O / Arbour, Mélanie / Sulea, Traian

Frontiers in molecular biosciences

2023 Volume 10, Page(s) 1253689

Abstract: Accurate protein-protein docking remains challenging, especially for artificial biologics not coevolved naturally against their protein targets, like antibodies and other engineered scaffolds. We previously developed ProPOSE, an exhaustive docker with ... ...

Abstract	Accurate protein-protein docking remains challenging, especially for artificial biologics not coevolved naturally against their protein targets, like antibodies and other engineered scaffolds. We previously developed ProPOSE, an exhaustive docker with full atomistic details, which delivers cutting-edge performance by allowing side-chain rearrangements upon docking. However, extensive protein backbone flexibility limits its practical applicability as indicated by unbound docking tests. To explore the usefulness of ProPOSE on systems with limited backbone flexibility, here we tested the engineered scaffold DARPin, which is characterized by its relatively rigid protein backbone. A prospective screening campaign was undertaken, in which sequence-diversified DARPins were docked and ranked against a directed epitope on the target protein BCL-W. In this proof-of-concept study, only a relatively small set of 2,213 diverse DARPin interfaces were selected for docking from the huge theoretical library from mutating 18 amino-acid positions. A computational selection protocol was then applied for enrichment of binders based on normalized computed binding scores and frequency of binding modes against the predefined epitope. The top-ranked 18 designed DARPin interfaces were selected for experimental validation. Three designs exhibited binding affinities to BCL-W in the nanomolar range comparable to control interfaces adopted from known DARPin binders. This result is encouraging for future screening and engineering campaigns of DARPins and possibly other similarly rigid scaffolds against targeted protein epitopes. Method limitations are discussed and directions for future refinements are proposed.
Language	English
Publishing date	2023-08-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2023.1253689
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