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Therapeutic Antibody Development: What Are We Learning along the Way?

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (15 November 2022) | Viewed by 52088

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Special Issue Editors

Dr. Anne Poupon

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Guest Editor

PRC, INRAe, CNRS, Université de Tours, INRIA, 37380 Nouzilly, France
Interests: bioinformatics; therapeutic antibodies; nanobodies
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Hervé Watier

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Co-Guest Editor

EA 7501 GICC, Université de Tours, 37032 Tours, France
Interests: structure/function relationship of antibodies; Fc variants
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

There is now ample evidence that monoclonal antibodies are very powerful drugs, fulfilling many unmet medical needs. There were only 20 approved recombinant antibodies in 2008, but this number has now reached more than 100, and hundreds are undergoing clinical trials, covering all therapeutic areas. As the properties needed for an antibody to be a good drug differ from those of natural and even pathogenic antibodies, many new scientific questions have arisen from pharmacological and pharmaceutical questions.

It clearly appears that, as often occurs in science, the more answers we bring, the more questions we get, making the discovery and development of therapeutic antibodies a perpetual questioning engine. The IgG1 subclass has been largely privileged, but many other natural or engineered heavy-chain isotypes are now available to adapt molecules to the pharmacological or pharmaceutical needs of long half-lives, reduced immunogenicity, reduced or sometimes increased immune activation, etc. A great effort of creativity has led to bi- or multispecific antibodies with totally new properties, bringing antigens, receptors and cells together. Observing and investigating the side effects of antibodies on very large cohorts has revealed off-target side effects, leading to the conclusion that antibodies are not as specific as we thought, reviving the questions of polyreactivity and polyspecificity. As we gain deeper knowledge on the mode of action, there is also increasing interest in playing with physico-chemical properties such as the pH dependence of either Fc-FcRn or Ag-Ab binding or even both. Another aspect is that, at present, the discovery and development process takes 5 to 10 years, with an attrition rate of 0.95. Many methods are being developed to secure and accelerate this process.

In this Special Issue, we will review some of these questions and how they may lead to important scientific advances. Papers related to any molecular aspects of antibodies, including bioinformatics studies, will be considered for this Special Issue.

Dr. Anne Poupon
Prof. Dr. Hervé Watier
Guest Editors

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Keywords

therapeutic antibodies
immunoglobulin isotypes
antibody physico-chemical properties
bioinformatics
antibody formats
FcRn
complement
pH dependence

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Therapeutic Antibody Development: What Are We Learning along the Way? 2.0 in International Journal of Molecular Sciences (5 articles)

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25 pages, 6816 KiB

Open AccessArticle

Rapid Generation and Molecular Docking Analysis of Single-Chain Fragment Variable (scFv) Antibody Selected by Ribosome Display Targeting Cholecystokinin B Receptor (CCK-BR) for Reduction of Chronic Neuropathic Pain

by Adinarayana Kunamneni, Marena A. Montera, Ravi Durvasula, Sascha R. A. Alles, Sachin Goyal and Karin N. Westlund

Int. J. Mol. Sci. 2023, 24(13), 11035; https://doi.org/10.3390/ijms241311035 - 3 Jul 2023

Cited by 3 | Viewed by 1883

Abstract

A robust cell-free platform technology, ribosome display in combination with cloning, expression, and purification was utilized to develop single chain Fragment variable (scFv) antibody variants as pain therapy directed at the mouse cholecystokinin B (CCK-B) receptor. Three effective CCK-B peptide-specific scFvs were generated through ribosomal display technology. Soluble expression and ELISA analysis showed that one antibody, scFv77-2 had the highest binding and could be purified from bacterial cells in large quantities. Octet measurements further revealed that the CCK-B scFv77-2 antibody had binding kinetics of K_D = 1.794 × 10^–8 M. Molecular modeling and docking analyses suggested that the scFv77-2 antibody shaped a proper cavity to embed the whole CCK-B peptide molecule and that a steady-state complex was formed relying on intermolecular forces, including hydrogen bonding, electrostatic force, and hydrophobic interactions. Thus, the scFv antibody can be applied for mechanistic intermolecular interactions and functional in vivo studies of CCK-BR. The high affinity scFv77-2 antibody showed good efficacy with binding to CCK-BR tested in a chronic pain model. In vivo studies validated the efficacy of the CCK-B receptor (CCK-BR) scFv77-2 antibody as a potential therapy for chronic trigeminal nerve injury-induced pain. Mice were given a single dose of the CCK-B receptor (CCK-BR) scFv antibody 3 weeks after induction of a chronic trigeminal neuropathic pain model, during the transition from acute to chronic pain. The long-term effectiveness for the reduction of mechanical hypersensitivity was evident, persisting for months. The anxiety- and depression-related behaviors typically accompanying persisting hypersensitivity subsequently never developed in the mice given CCK-BR scFv. The effectiveness of the antibody is the basis for further development of the lead CCK-BR scFv as a promising non-opioid therapeutic for chronic pain and the long-term reduction of chronic pain- and anxiety-related behaviors. Full article

(This article belongs to the Special Issue Therapeutic Antibody Development: What Are We Learning along the Way?)

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13 pages, 2756 KiB

Open AccessArticle

Efficient Production of Fc Fusion Proteins in the Cytoplasm of Escherichia coli: Dissecting and Mitigating Redox Heterogeneity

by Aatir A. Tungekar and Lloyd W. Ruddock

Int. J. Mol. Sci. 2022, 23(23), 14740; https://doi.org/10.3390/ijms232314740 - 25 Nov 2022

Cited by 2 | Viewed by 3456

Abstract

Cost-effective production of therapeutic proteins in microbial hosts is an indispensable tool towards accessible healthcare. Many of these heterologously expressed proteins, including all antibody formats, require disulfide bond formation to attain their native and functional state. A system for catalyzed disulfide bond formation (CyDisCo) has been developed allowing efficient production of recombinant proteins in the cytoplasm of one of the most used microbial expression systems, Escherichia coli. Here, we report high-yield production (up to 230 mg/L from 3 mL cultures) of in-demand therapeutics such as IgG₁-based Fc fusion proteins in the E. coli cytoplasm. However, the production of this drug class using the CyDisCo system faces bottlenecks related to redox heterogeneity during oxidative folding. Our investigations identified and addressed one of the major causes of redox heterogeneity during CyDisCo-based production of Fc fusion proteins, i.e., disulfide bond formation in the IgG₁ C_H3 domain. Here, we communicate that mutating the cysteines in the C_H3 domain of target Fc fusion proteins allows their production in a homogeneous redox state in the cytoplasm of E. coli without compromising on yields and thermal stability. Full article

(This article belongs to the Special Issue Therapeutic Antibody Development: What Are We Learning along the Way?)

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14 pages, 1980 KiB

Open AccessArticle

Development of Anti-LRRC15 Small Fragments for Imaging Purposes Using a Phage-Display ScFv Approach

by Pierre-Emmanuel Baurand, Jérémy Balland, Chloé Reynas, Mélanie Ramseyer, Delphine Vivier, Pierre-Simon Bellaye, Bertrand Collin, Catherine Paul, Franck Denat, Kamal Asgarov, Jean-René Pallandre and Laurence Ringenbach

Int. J. Mol. Sci. 2022, 23(20), 12677; https://doi.org/10.3390/ijms232012677 - 21 Oct 2022

Cited by 4 | Viewed by 2876

Abstract

The human leucine-rich repeat-containing protein 15 (LRRC15) is a membrane protein identified as a marker of CAF (cancer-associated fibroblast) cells whose overexpression is positively correlated with cancer grade and outcome. Nuclear molecular imaging (i.e., SPECT and PET) to track LRRC15 expression could be very useful in guiding further therapeutic strategies. In this study, we developed an ScFv mouse phage-display library to obtain small fragment antibodies against human LRRC15 for molecular imaging purposes. Mice were immunized with recombinant human LRRC15 (hLRRC15), and lymph node cells were harvested for ScFv (single-chain variable fragment) phage-display analysis. The built library was used for panning on cell lines with constitutive or induced expression after transfection. The choice of best candidates was performed by screening various other cell lines, using flow cytometry. The selected candidates were reformatted into Cys-ScFv or Cys-diabody by addition of cysteine, and cloned in mammalian expression vectors to obtain batches of small fragments that were further used in site-specific radiolabeling tests. The obtained library was 1.2 × 10⁷ cfu/µg with an insertion rate >95%. The two panning rounds performed on cells permittedenrichment of 2 × 10⁻³. Screening with flow cytometry allowed us to identify 28 specific hLRRC15 candidates. Among these, two also recognized murine LRCC15 and were reformatted into Cys-ScFv and Cys-diabody. They were expressed transiently in a mammalian system to obtain 1.0 to 4.5 mg of Cys fragments ready for bioconjugation and radiolabeling. Thus, in this paper, we demonstrate the relevance of the phage-display ScFv library approach for the fast-track development of small antibodies for imaging and/or immunotherapy purposes. Full article

(This article belongs to the Special Issue Therapeutic Antibody Development: What Are We Learning along the Way?)

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17 pages, 5077 KiB

Open AccessArticle

A New in Silico Antibody Similarity Measure Both Identifies Large Sets of Epitope Binders with Distinct CDRs and Accurately Predicts Off-Target Reactivity

by Astrid Musnier, Thomas Bourquard, Amandine Vallet, Laetitia Mathias, Gilles Bruneau, Mohammed Akli Ayoub, Ophélie Travert, Yannick Corde, Nathalie Gallay, Thomas Boulo, Sandra Cortes, Hervé Watier, Pascale Crépieux, Eric Reiter and Anne Poupon

Int. J. Mol. Sci. 2022, 23(17), 9765; https://doi.org/10.3390/ijms23179765 - 28 Aug 2022

Cited by 7 | Viewed by 2810

Abstract

Developing a therapeutic antibody is a long, tedious, and expensive process. Many obstacles need to be overcome, such as biophysical properties (issues of solubility, stability, weak production yields, etc.), as well as cross-reactivity and subsequent toxicity, which are major issues. No in silico method exists today to solve such issues. We hypothesized that if we were able to properly measure the similarity between the CDRs of antibodies (Ab) by considering not only their evolutionary proximity (sequence identity) but also their structural features, we would be able to identify families of Ab recognizing similar epitopes. As a consequence, Ab within the family would share the property to recognize their targets, which would allow (i) to identify off-targets and forecast the cross-reactions, and (ii) to identify new Ab specific for a given target. Testing our method on 238D2, an antagonistic anti-CXCR4 nanobody, we were able to find new nanobodies against CXCR4 and to identify influenza hemagglutinin as an off-target of 238D2. Full article

(This article belongs to the Special Issue Therapeutic Antibody Development: What Are We Learning along the Way?)

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15 pages, 1332 KiB

Open AccessArticle

Distinct Longitudinal Changes in Immunoglobulin G N-Glycosylation Associate with Therapy Response in Chronic Inflammatory Diseases

by Jerko Štambuk, Frano Vučković, Siniša Habazin, Maja Hanić, Mislav Novokmet, Susanna Nikolaus, Florian Tran, Stefan Schreiber, Andre Franke, Philip Rosenstiel, Gordan Lauc, Konrad Aden and Marija Pezer

Int. J. Mol. Sci. 2022, 23(15), 8473; https://doi.org/10.3390/ijms23158473 - 30 Jul 2022

Cited by 8 | Viewed by 3467

Abstract

Immunosuppressants and biologicals are widely used therapeutics for various chronic inflammatory diseases (CID). To gain more detailed insight into their downstream effects, we examined their impact on serum immunoglobulin G (IgG) glycosylation. We analyzed IgG subclass-specific fragment crystallizable (Fc) N-glycosylation in patients suffering from various CID using the LC-MS approach. Firstly, we compared IgG Fc N-glycosylation between 128 CID patients and 204 healthy controls. Our results replicated previously observed CID-related decrease in IgG Fc galactosylation (adjusted p-value range 1.70 × 10⁻²–5.95 × 10⁻²²) and sialylation (adjusted p-value range 1.85 × 10⁻²–1.71 × 10⁻¹⁸). Secondly, to assess changes in IgG Fc N-glycosylation associated with therapy and remission status, we compared 139 CID patients receiving either azathioprine, infliximab, or vedolizumab therapy. We observed an increase in IgG Fc galactosylation (adjusted p-value range 1.98 × 10⁻²–1.30 × 10⁻¹⁵) and sialylation (adjusted p-value range 3.28 × 10⁻⁶–4.34 × 10⁻¹⁸) during the treatment. Furthermore, patients who reached remission displayed increased Fc galactosylation levels (p-value range 2.25 × 10⁻²–5.44 × 10⁻³) in comparison to patients with active disease. In conclusion, the alterations in IgG Fc glycosylation and the fact these changes are even more pronounced in patients who achieved remission, suggest modulation of IgG inflammatory potential associated with CID therapy. Full article

(This article belongs to the Special Issue Therapeutic Antibody Development: What Are We Learning along the Way?)

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23 pages, 4913 KiB

Open AccessArticle

A Broad-Based Characterization of a Cell-Penetrating, Single Domain Camelid Bi-Specific Antibody Monomer That Targets STAT3 and KRAS Dependent Cancers

by Sunanda Singh, Genoveva Murillo, Justin Richner, Samara P. Singh, Erica Berleth, Vijay Kumar, Rajendra Mehta, Vijay Ramiya and Ashutosh S. Parihar

Int. J. Mol. Sci. 2022, 23(14), 7565; https://doi.org/10.3390/ijms23147565 - 8 Jul 2022

Cited by 4 | Viewed by 3410

Abstract

STAT3 and KRAS regulate cell proliferation, survival, apoptosis, cell migration, and angiogenesis. Aberrant expression of STAT3 and mutant active forms of KRAS have been well-established in the induction and maintenance of multiple cancers. STAT3 and KRAS mutant proteins have been considered anti-cancer targets; however, they are also considered to be clinically “undruggable” intracellular molecules, except for KRAS(G12C). Here we report a first-in-class molecule, a novel, single domain camelid VHH antibody (15 kDa), SBT-100, that binds to both STAT3 and KRAS and can penetrate the tumor cell membrane, and significantly inhibit cancer cell growth. Additionally, SBT-100 inhibits KRAS GTPase activity and downstream phosphorylation of ERK in vitro. In addition, SBT-100 inhibits the growth of multiple human cancers in vitro and in vivo. These results demonstrate the feasibility of targeting hard-to-reach aberrant intracellular transcription factors and signaling proteins simultaneously with one VHH to improve cancer therapies. Full article

(This article belongs to the Special Issue Therapeutic Antibody Development: What Are We Learning along the Way?)

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28 pages, 7037 KiB

Open AccessArticle

Human Superantibodies to 3CL^pro Inhibit Replication of SARS-CoV-2 across Variants

by Kittirat Glab-ampai, Kanasap Kaewchim, Thanatsaran Saenlom, Watayagorn Thepsawat, Kodchakorn Mahasongkram, Nitat Sookrung, Wanpen Chaicumpa and Monrat Chulanetra

Int. J. Mol. Sci. 2022, 23(12), 6587; https://doi.org/10.3390/ijms23126587 - 13 Jun 2022

Cited by 5 | Viewed by 2359

Abstract

Broadly effective and safe anti-coronavirus agent is existentially needed. Major protease (3CL^pro) is a highly conserved enzyme of betacoronaviruses. The enzyme plays pivotal role in the virus replication cycle. Thus, it is a good target of a broadly effective anti-Betacoronavirus agent. In this study, human single-chain antibodies (HuscFvs) of the SARS-CoV-2 3CL^pro were generated using phage display technology. The 3CL^pro-bound phages were used to infect Escherichia coli host for the production the 3CL^pro-bound HuscFvs. Computerized simulation was used to guide the selection of the phage infected-E. coli clones that produced HuscFvs with the 3CL^pro inhibitory potential. HuscFvs of three phage infected-E. coli clones were predicted to form contact interface with residues for 3CL^pro catalytic activity, substrate binding, and homodimerization. These HuscFvs were linked to a cell-penetrating peptide to make them cell-penetrable, i.e., became superantibodies. The superantibodies blocked the 3CL^pro activity in vitro, were not toxic to human cells, traversed across membrane of 3CL^pro-expressing cells to co-localize with the intracellular 3CL^pro and most of all, they inhibited replication of authentic SARS-CoV-2 Wuhan wild type and α, β, δ, and Omicron variants that were tested. The superantibodies should be investigated further towards clinical application as a safe and broadly effective anti-Betacoronavirus agent. Full article

(This article belongs to the Special Issue Therapeutic Antibody Development: What Are We Learning along the Way?)

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15 pages, 5633 KiB

Open AccessArticle

Development of a Novel Anti−CD44 Monoclonal Antibody for Multiple Applications against Esophageal Squamous Cell Carcinomas

by Nohara Goto, Hiroyuki Suzuki, Tomohiro Tanaka, Teizo Asano, Mika K. Kaneko and Yukinari Kato

Int. J. Mol. Sci. 2022, 23(10), 5535; https://doi.org/10.3390/ijms23105535 - 16 May 2022

Cited by 12 | Viewed by 3451

Abstract

CD44 is a cell surface glycoprotein, which is expressed on normal cells, and overexpressed on cancer cells. CD44 is involved in cell adhesion, migration, proliferation, survival, stemness, and chemo−resistance. Therefore, CD44 is thought to be a promising target for cancer diagnosis and therapy. In this study, we established anti−CD44 monoclonal antibodies (mAbs) by immunizing mice with a CD44 variant (CD44v3−10) ectodomain and screening using enzyme−linked immunosorbent assay. We then characterized them using flow cytometry, Western blotting, and immunohistochemistry. One of the established clones (C₄₄Mab−46; IgG₁, kappa) reacted with CD44 standard isoform (CD44s)−overexpressed Chinese hamster ovary−K1 cells (CHO/CD44s) or esophageal squamous cell carcinoma (ESCC) cell lines (KYSE70 and KYSE770). The apparent K_D of C₄₄Mab−46 for CHO/CD44s, KYSE70, and KYSE770 was 1.1 × 10⁻⁸ M, 4.9 × 10⁻⁸ M, and 4.1 × 10⁻⁸ M, respectively. C₄₄Mab−46 detected CD44s of CHO/CD44s and KYSE70, and CD44 variants of KYSE770 in Western blot analysis. Furthermore, C₄₄Mab−46 strongly stained the formalin−fixed paraffin−embedded ESCC tissues in immunohistochemistry. Collectively, C₄₄Mab−46 is very useful for detecting CD44 in various applications. Full article

(This article belongs to the Special Issue Therapeutic Antibody Development: What Are We Learning along the Way?)

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Review

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28 pages, 841 KiB

Open AccessReview

Targeting the Brain with Single-Domain Antibodies: Greater Potential Than Stated So Far?

by Mireille Elodie Tsitokana, Pierre-André Lafon, Laurent Prézeau, Jean-Philippe Pin and Philippe Rondard

Int. J. Mol. Sci. 2023, 24(3), 2632; https://doi.org/10.3390/ijms24032632 - 30 Jan 2023

Cited by 6 | Viewed by 5565

Abstract

Treatments for central nervous system diseases with therapeutic antibodies have been increasingly investigated over the last decades, leading to some approved monoclonal antibodies for brain disease therapies. The detection of biomarkers for diagnosis purposes with non-invasive antibody-based imaging approaches has also been explored in brain cancers. However, antibodies generally display a low capability of reaching the brain, as they do not efficiently cross the blood−brain barrier. As an alternative, recent studies have focused on single-domain antibodies (sdAbs) that correspond to the antigen-binding fragment. While some reports indicate that the brain uptake of these small antibodies is still low, the number of studies reporting brain-penetrating sdAbs is increasing. In this review, we provide an overview of methods used to assess or evaluate brain penetration of sdAbs and discuss the pros and cons that could affect the identification of brain-penetrating sdAbs of therapeutic or diagnostic interest. Full article

(This article belongs to the Special Issue Therapeutic Antibody Development: What Are We Learning along the Way?)

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22 pages, 2589 KiB

Open AccessReview

Review of the Existing Translational Pharmacokinetics Modeling Approaches Specific to Monoclonal Antibodies (mAbs) to Support the First-In-Human (FIH) Dose Selection

by Blaise Pasquiers, Salih Benamara, Mathieu Felices, Laurent Nguyen and Xavier Declèves

Int. J. Mol. Sci. 2022, 23(21), 12754; https://doi.org/10.3390/ijms232112754 - 22 Oct 2022

Cited by 7 | Viewed by 4923

Abstract

The interest in therapeutic monoclonal antibodies (mAbs) has continuously growing in several diseases. However, their pharmacokinetics (PK) is complex due to their target-mediated drug disposition (TMDD) profiles which can induce a non-linear PK. This point is particularly challenging during the pre-clinical and translational development of a new mAb. This article reviews and describes the existing PK modeling approaches used to translate the mAbs PK from animal to human for intravenous (IV) and subcutaneous (SC) administration routes. Several approaches are presented, from the most empirical models to full physiologically based pharmacokinetic (PBPK) models, with a focus on the population PK methods (compartmental and minimal PBPK models). They include the translational approaches for the linear part of the PK and the TMDD mechanism of mAbs. The objective of this article is to provide an up-to-date overview and future perspectives of the translational PK approaches for mAbs during a model-informed drug development (MIDD), since the field of PK modeling has gained recently significant interest for guiding mAbs drug development. Full article

(This article belongs to the Special Issue Therapeutic Antibody Development: What Are We Learning along the Way?)

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14 pages, 2074 KiB

Open AccessReview

Finding the Right Heavy Chains for Immunostimulatory Antibodies

by Pierre Boulard, Valérie Gouilleux-Gruart and Hervé Watier

Int. J. Mol. Sci. 2022, 23(18), 10367; https://doi.org/10.3390/ijms231810367 - 8 Sep 2022

Cited by 5 | Viewed by 2763

Abstract

For twelve years, the oncology field has been revolutionized by antibodies targeting immune checkpoints. They must be considered as a heterogenous family of immunostimulatory antibodies displaying very different mechanisms of action, not only depending on the target or on the cells expressing it, but also on the IgG subclass or IgG variant that has been chosen. To dissect this complex landscape, the clinical experience has been confronted with a precise analysis of the heavy chain isotypes, referred as new Ge nomenclature. For antibodies targeting inhibitory receptors, anti-CTLA-4 antibodies (whose main effect is to kill regulatory T cells) will be distinguished from anti-PD-1 antibodies and other true antagonistic antibodies. Antibodies targeting ligands of inhibitory receptors (PD-L1, CD47) represent another different category, due to the antigen expression on tumors and a possible beneficial killing effect. The case of agonistic antibodies targeting lymphocyte activatory receptors, such as CD40 or 4-1BB, is still another “under construction” category because these products are less advanced in their clinical development. Altogether, it appears that choosing the right heavy chain is crucial to obtain the desired pharmacological effect in patients. Full article

(This article belongs to the Special Issue Therapeutic Antibody Development: What Are We Learning along the Way?)

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12 pages, 1002 KiB

Open AccessReview

Monoclonal Antibody Engineering and Design to Modulate FcRn Activities: A Comprehensive Review

by Yanis Ramdani, Juliette Lamamy, Hervé Watier and Valérie Gouilleux-Gruart

Int. J. Mol. Sci. 2022, 23(17), 9604; https://doi.org/10.3390/ijms23179604 - 24 Aug 2022

Cited by 17 | Viewed by 7134

Abstract

Understanding the biological mechanisms underlying the pH-dependent nature of FcRn binding, as well as the various factors influencing the affinity to FcRn, was concurrent with the arrival of the first recombinant IgG monoclonal antibodies (mAbs) and IgG Fc-fusion proteins in clinical practice. IgG Fc–FcRn became a central subject of interest for the development of these drugs for the comfort of patients and good clinical responses. In this review, we describe (i) mAb mutations close to and outside the FcRn binding site, increasing the affinity for FcRn at acidic pH and leading to enhanced mAb half-life and biodistribution, and (ii) mAb mutations increasing the affinity for FcRn at acidic and neutral pH, blocking FcRn binding and resulting, in vivo, in endogenous IgG degradation. Mutations modifying FcRn binding are discussed in association with pH-dependent modulation of antigen binding and (iii) anti-FcRn mAbs, two of the latest innovations in anti-FcRn mAbs leading to endogenous IgG depletion. We discuss the pharmacological effects, the biological consequences, and advantages of targeting IgG–FcRn interactions and their application in human therapeutics. Full article

(This article belongs to the Special Issue Therapeutic Antibody Development: What Are We Learning along the Way?)

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13 pages, 422 KiB

Open AccessReview

Recent Advances and Future Directions in Downstream Processing of Therapeutic Antibodies

by Allan Matte

Int. J. Mol. Sci. 2022, 23(15), 8663; https://doi.org/10.3390/ijms23158663 - 4 Aug 2022

Cited by 18 | Viewed by 6364

Abstract

Despite the advent of many new therapies, therapeutic monoclonal antibodies remain a prominent biologics product, with a market value of billions of dollars annually. A variety of downstream processing technological advances have led to a paradigm shift in how therapeutic antibodies are developed and manufactured. A key driver of change has been the increased adoption of single-use technologies for process development and manufacturing. An early-stage developability assessment of potential lead antibodies, using both in silico and high-throughput experimental approaches, is critical to de-risk development and identify molecules amenable to manufacturing. Both statistical and mechanistic modelling approaches are being increasingly applied to downstream process development, allowing for deeper process understanding of chromatographic unit operations. Given the greater adoption of perfusion processes for antibody production, continuous and semi-continuous downstream processes are being increasingly explored as alternatives to batch processes. As part of the Quality by Design (QbD) paradigm, ever more sophisticated process analytical technologies play a key role in understanding antibody product quality in real-time. We should expect that computational prediction and modelling approaches will continue to be advanced and exploited, given the increasing sophistication and robustness of predictive methods compared to the costs, time, and resources required for experimental studies. Full article

(This article belongs to the Special Issue Therapeutic Antibody Development: What Are We Learning along the Way?)

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