ijms-logo

Journal Browser

Journal Browser

Therapeutic Antibody Development: What Are We Learning along the Way? 2.0

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

Deadline for manuscript submissions: closed (15 November 2023) | Viewed by 11761

Special Issue Editors


E-Mail Website
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

E-Mail Website
Guest Editor
EA 7501 GICC, Université de Tours, 37032 Tours, France
Interests: structure/function relationship of antibodies; Fc variants

Special Issue Information

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

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

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

Benefits of Publishing in a Special Issue

  • Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
  • Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
  • Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
  • External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
  • e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue polices can be found here.

Related Special Issue

Published Papers (5 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Research

18 pages, 4104 KiB  
Article
Generation and Characterization of SORT1-Targeted Antibody–Drug Conjugate for the Treatment of SORT1-Positive Breast Tumor
by Weiliang Zhuang, Wei Zhang, Liping Xie, Lei Wang, Yuan Li, Ziyu Wang, Ao Zhang, Haitao Qiu, Jun Feng, Baohong Zhang and Youjia Hu
Int. J. Mol. Sci. 2023, 24(24), 17631; https://doi.org/10.3390/ijms242417631 - 18 Dec 2023
Cited by 1 | Viewed by 2219
Abstract
Antibody–drug conjugates (ADCs) have greatly improved the outcomes of advanced breast tumors. However, the treatment of breast tumors with existing ADCs is still hindered by many issues, such as tumor antigen heterogeneity and drug resistance. Therefore, ADCs against new targets would provide options [...] Read more.
Antibody–drug conjugates (ADCs) have greatly improved the outcomes of advanced breast tumors. However, the treatment of breast tumors with existing ADCs is still hindered by many issues, such as tumor antigen heterogeneity and drug resistance. Therefore, ADCs against new targets would provide options for the treatment of these challenges. Sortilin-1 (SORT1) may be a promising target for ADC as it is upregulated in breast cancer. To evaluate the possibility of SORT1 as an ADC target, a humanized antibody_8D302 with high affinity against SORT1 was generated. Additionally, 8D302 was conjugated with MMAE and DXd to generate two ADCs_8D302-MMAE and 8D302-DXd, respectively. Both 8D302-MMAE and 8D302-DXd showed effective cytotoxicity against SORT1 positive breast tumor cell lines and induced bystander killing. Consequently, 8D302-MMAE showed relatively better anti-tumor activity than 8D302-DXd both in vitro and in vivo, but 8D302-DXd had superior safety profile and pharmacokinetics profile over 8D302-MMAE. Furthermore, SORT1 induced faster internalization and lysosomal trafficking of antibodies and had a higher turnover compared with HER2. Also, 8D302-DXd exhibited superior cell cytotoxicity and tumor suppression over trastuzumab-DXd, a HER2-targeted ADC. We hypothesize that the high turnover of SORT1 enables SORT1-targeted ADC to be a powerful agent for the treatment of SORT1-positive breast tumor. Full article
Show Figures

Figure 1

20 pages, 2059 KiB  
Article
No Interference of H9 Extract on Trastuzumab Pharmacokinetics in Their Combinations
by Seung Yon Han, Jeong-Eun Yu, Byoung Hoon You, Seo-Yeon Kim, Mingoo Bae, Hee-Sung Chae, Young-Won Chin, Soo-Hwa Hong, Ju-Hee Lee, Seung Hyun Jung and Young Hee Choi
Int. J. Mol. Sci. 2023, 24(23), 16677; https://doi.org/10.3390/ijms242316677 - 23 Nov 2023
Viewed by 1294
Abstract
Trastuzumab is used to treat breast cancer patients overexpressing human epidermal growth factor receptor 2, but resistance and toxicity limit its uses, leading to attention to trastuzumab combinations. Recently, the synergistic effect of trastuzumab and H9 extract (H9) combination against breast cancer has [...] Read more.
Trastuzumab is used to treat breast cancer patients overexpressing human epidermal growth factor receptor 2, but resistance and toxicity limit its uses, leading to attention to trastuzumab combinations. Recently, the synergistic effect of trastuzumab and H9 extract (H9) combination against breast cancer has been reported. Because drug exposure determines its efficacy and toxicity, the question of whether H9 changes trastuzumab exposure in the body has been raised. Therefore, this study aimed to characterize trastuzumab pharmacokinetics and elucidate the effect of H9 on trastuzumab pharmacokinetics at a combination dose that shows synergism in mice. As a result, trastuzumab showed linear pharmacokinetics after its intravenous administration from 1 to 10 mg/kg. In the combination of trastuzumab and H9, single and 2-week treatments of oral H9 (500 mg/kg) did not influence trastuzumab pharmacokinetics. In the multiple-combination treatments of trastuzumab and H9 showing their synergistic effect (3 weeks of trastuzumab with 2 weeks of H9), the pharmacokinetic profile of trastuzumab was comparable to that of 3 weeks of trastuzumab alone. In tissue distribution, the tissue to plasma ratios of trastuzumab below 1.0 indicated its limited distributions within the tissues, and these patterns were unaffected by H9. These results suggest that the systemic and local exposures of trastuzumab are unchanged by single and multiple-combination treatments of H9. Full article
Show Figures

Figure 1

17 pages, 3390 KiB  
Article
Longitudinal Variations in Antibody Responses against SARS-CoV-2 Spike Epitopes upon Serial Vaccinations
by Dicle Yalcin, Sydney J. Bennett, Jared Sheehan, Amber J. Trauth, For Yue Tso, John T. West, Michael E. Hagensee, Alistair J. Ramsay and Charles Wood
Int. J. Mol. Sci. 2023, 24(8), 7292; https://doi.org/10.3390/ijms24087292 - 14 Apr 2023
Cited by 6 | Viewed by 2969
Abstract
The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impacted healthcare, the workforce, and worldwide socioeconomics. Multi-dose mono- or bivalent mRNA vaccine regimens have shown high efficacy in protection against SARS-CoV-2 and its emerging variants with varying degrees of [...] Read more.
The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impacted healthcare, the workforce, and worldwide socioeconomics. Multi-dose mono- or bivalent mRNA vaccine regimens have shown high efficacy in protection against SARS-CoV-2 and its emerging variants with varying degrees of efficacy. Amino acid changes, primarily in the receptor-binding domain (RBD), result in selection for viral infectivity, disease severity, and immune evasion. Therefore, many studies have centered around neutralizing antibodies that target the RBD and their generation achieved through infection or vaccination. Here, we conducted a unique longitudinal study, analyzing the effects of a three-dose mRNA vaccine regimen exclusively using the monovalent BNT162b2 (Pfizer/BioNTech) vaccine, systematically administered to nine previously uninfected (naïve) individuals. We compare changes in humoral antibody responses across the entire SARS-CoV-2 spike glycoprotein (S) using a high-throughput phage display technique (VirScan). Our data demonstrate that two doses of vaccination alone can achieve the broadest and highest magnitudes of anti-S response. Moreover, we present evidence of novel highly boosted non-RBD epitopes that strongly correlate with neutralization and recapitulate independent findings. These vaccine-boosted epitopes could facilitate multi-valent vaccine development and drug discovery. Full article
Show Figures

Figure 1

16 pages, 3082 KiB  
Article
Influence of Genetics on the Response to Omalizumab in Patients with Severe Uncontrolled Asthma with an Allergic Phenotype
by Susana Rojo-Tolosa, José Antonio Sánchez-Martínez, Laura Elena Pineda-Lancheros, José María Gálvez-Navas, María Victoria González-Gutiérrez, Gonzalo Jiménez-Gálvez, Cristina Pérez-Ramírez, Concepción Morales-García and Alberto Jiménez-Morales
Int. J. Mol. Sci. 2023, 24(8), 7029; https://doi.org/10.3390/ijms24087029 - 10 Apr 2023
Cited by 3 | Viewed by 2602
Abstract
Omalizumab is a monoclonal antibody indicated for the treatment of severe uncontrolled asthma with an allergic phenotype. Its effectiveness could be influenced by clinical variables and single nucleotide polymorphisms (SNPs) in one or more of the genes involved in the mechanism of action [...] Read more.
Omalizumab is a monoclonal antibody indicated for the treatment of severe uncontrolled asthma with an allergic phenotype. Its effectiveness could be influenced by clinical variables and single nucleotide polymorphisms (SNPs) in one or more of the genes involved in the mechanism of action and process of response to omalizumab, and these could be used as predictive biomarkers of response. We conducted an observational retrospective cohort study that included patients with severe uncontrolled allergic asthma treated with omalizumab in a tertiary hospital. Satisfactory response after 12 months of treatment was defined as (1) Reduction ≥ 50% of exacerbations or no exacerbations, (2) Improvement of lung function ≥ 10% FEV1, and (3) Reduction ≥ 50% of OCS courses or no OCS. Polymorphisms in the FCER1A (rs2251746, rs2427837), FCER1B (rs1441586, rs573790, rs1054485, rs569108), C3 (rs2230199), FCGR2A (rs1801274), FCGR2B (rs3219018, rs1050501), FCGR3A (rs10127939, rs396991), IL1RL1 (rs1420101, rs17026974, rs1921622), and GATA2 (rs4857855) genes were analyzed by real-time polymerase chain reaction (PCR) using TaqMan probes. A total of 110 patients under treatment with omalizumab were recruited. After 12 months of treatment, the variables associated with a reduction in exacerbations were the absence of polyposis (odds ratio [OR] = 4.22; 95% confidence interval [CI] = 0.95–19.63), IL1RL1 rs17026974-AG (OR = 19.07; 95% CI = 1.27–547), and IL1RL1 rs17026974-GG (OR = 16.76; 95% CI = 1.22–438.76). Reduction in oral corticosteroids (OCS) was associated with age of starting omalizumab treatment (OR = 0.95; 95% CI = 0.91–0.99) and blood eosinophil levels > 300 cells/µL (OR = 2.93; 95% CI = 1.01–9.29). Improved lung function showed a relationship to the absence of chronic obstructive pulmonary disease (COPD) (OR = 12.16; 95% CI = 2.45–79.49), FCGR2B rs3219018-C (OR = 8.6; 95% CI = 1.12–117.15), GATA2 rs4857855-T (OR = 15.98; 95% CI = 1.52–519.57) and FCGR2A rs1801274-G (OR = 13.75; 95% CI = 2.14–142.68; AG vs. AA and OR = 7.46; 95% CI = 0.94–89.12; GG vs. AA). Meeting one response criterion was related to FCER1A rs2251746-TT (OR = 24; 95% CI = 0.77–804.57), meeting two to age of asthma diagnosis (OR = 0.93; 95% CI = 0.88–0.99), and meeting all three to body mass index (BMI) < 25 (OR = 14.23; 95% CI = 3.31–100.77) and C3 rs2230199-C (OR = 3; 95% CI = 1.01–9.92). The results of this study show the possible influence of the polymorphisms studied on the response to omalizumab and the clinical benefit that could be obtained by defining predictive biomarkers of treatment response. Full article
Show Figures

Figure 1

40 pages, 2874 KiB  
Article
Harnessing Fc/FcRn Affinity Data from Patents with Different Machine Learning Methods
by Christophe Dumet, Martine Pugnière, Corinne Henriquet, Valérie Gouilleux-Gruart, Anne Poupon and Hervé Watier
Int. J. Mol. Sci. 2023, 24(6), 5724; https://doi.org/10.3390/ijms24065724 - 16 Mar 2023
Viewed by 2136
Abstract
Monoclonal antibodies are biopharmaceuticals with a very long half-life due to the binding of their Fc portion to the neonatal receptor (FcRn), a pharmacokinetic property that can be further improved through engineering of the Fc portion, as demonstrated by the approval of several [...] Read more.
Monoclonal antibodies are biopharmaceuticals with a very long half-life due to the binding of their Fc portion to the neonatal receptor (FcRn), a pharmacokinetic property that can be further improved through engineering of the Fc portion, as demonstrated by the approval of several new drugs. Many Fc variants with increased binding to FcRn have been found using different methods, such as structure-guided design, random mutagenesis, or a combination of both, and are described in the literature as well as in patents. Our hypothesis is that this material could be subjected to a machine learning approach in order to generate new variants with similar properties. We therefore compiled 1323 Fc variants affecting the affinity for FcRn, which were disclosed in twenty patents. These data were used to train several algorithms, with two different models, in order to predict the affinity for FcRn of new randomly generated Fc variants. To determine which algorithm was the most robust, we first assessed the correlation between measured and predicted affinity in a 10-fold cross-validation test. We then generated variants by in silico random mutagenesis and compared the prediction made by the different algorithms. As a final validation, we produced variants, not described in any patents, and compared the predicted affinity with the experimental binding affinities measured by surface plasmon resonance (SPR). The best mean absolute error (MAE) between predicted and experimental values was obtained with a support vector regressor (SVR) using six features and trained on 1251 examples. With this setting, the error on the log(KD) was less than 0.17. The obtained results show that such an approach could be used to find new variants with better half-life properties that are different from those already extensively used in therapeutic antibody development. Full article
Show Figures

Figure 1

Back to TopTop