Therapeutic monoclonal antibodies for respiratory diseases: Current challenges and perspectives, March 31 – April 1, 2016, Tours, France

Désoubeaux, Guillaume; Reichert, Janice M.; Sleeman, Matthew A.; Reckamp, Karen L.; Ryffel, Bernhard; Adamczewski, J P; Sweeney, Theresa D.; Vanbever, Rita; Diot, Patrice; Owen, Caroline A.; Page, Clive; Lerondel, Stéphanie; Pape, Alain Le; Heuzé-Vourc’h, Nathalie

doi:10.1080/19420862.2016.1196521

Cited by 38 publications

(38 citation statements)

References 62 publications

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“…For example, transient expression levels for monomeric IgA have been reported for human IgA1 or IgA2m1 isotypes at 30-70 µg/L. 25 To overcome these low production yields, stable cell lines have increased expression levels of monomeric IgA1, IgA2m1 and IgA2m2 to 110-190 mg/L. 26 Whereas human IgG1 typically has only two N-linked glycosylation sites, one in each C H 2 domain, human IgA contains multiple glycosylation sites that can be susceptible to glycan heterogeneity.…”

Section: Introductionmentioning

confidence: 99%

Production, characterization, andin vivohalf-life extension of polymeric IgA molecules in mice

Lombana¹,

Rajan²,

Zorn³

et al. 2019

mAbs

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IgA antibodies have broad potential as a novel therapeutic platform based on their superior receptor-mediated cytotoxic activity, potent neutralization of pathogens, and ability to transcytose across mucosal barriers via polymeric immunoglobulin receptor (pIgR)-mediated transport, compared to traditional IgG-based drugs. However, the transition of IgA into clinical development has been challenged by complex expression and characterization, as well as rapid serum clearance that is thought to be mediated by glycan receptor scavenging of recombinantly produced IgA monomer bearing incompletely sialylated N-linked glycans. Here, we present a comprehensive biochemical, biophysical, and structural characterization of recombinantly produced monomeric, dimeric and polymeric human IgA. We further explore two strategies to overcome the rapid serum clearance of polymeric IgA: removal of all N-linked glycosylation sites creating an aglycosylated polymeric IgA and engineering in FcRn binding with the generation of a polymeric IgG-IgA Fc fusion. While previous reports and the results presented in this study indicate that glycan-mediated clearance plays a major role for monomeric IgA, systemic clearance of polymeric IgA in mice is predominantly controlled by mechanisms other than glycan receptor clearance, such as pIgR-mediated transcytosis. The developed IgA platform now provides the potential to specifically target pIgR expressing tissues, while maintaining low systemic exposure.

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Section: Introductionmentioning

confidence: 99%

Production, characterization, andin vivohalf-life extension of polymeric IgA molecules in mice

Lombana¹,

Rajan²,

Zorn³

et al. 2019

mAbs

View full text Add to dashboard Cite

show abstract

“…As an example, in the past two years two monoclonal antibodies (mepolizumab and reslizumab) received approval for severe asthma, providing further options for the treatment of severe asthma. When considering the administration of large drug molecules, like biotherapeutics, matching the delivery route to the relevant anatomical location is paramount (Desoubeaux et al, 2016). The delivery of drugs for treating respiratory diseases by inhalation has long been considered to allow a rapid onset of action, to ensure a high concentration of drugs in the vicinity of the relevant anatomical region while limiting systemic exposure and reducing the likelihood of side-effects.…”

Section: Introductionmentioning

confidence: 99%

Insights on animal models to investigate inhalation therapy: Relevance for biotherapeutics

Guillon

Sécher

Dailey

et al. 2018

International Journal of Pharmaceutics

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Acute and chronic respiratory diseases account for major causes of illness and deaths worldwide. Recent developments of biotherapeutics opened a new era in the treatment and management of patients with respiratory diseases. When considering the delivery of therapeutics, the inhaled route offers great promises with a direct, non-invasive access to the diseased organ and has already proven efficient for several molecules. To assist in the future development of inhaled biotherapeutics, experimental models are crucial to assess lung deposition, pharmacokinetics, pharmacodynamics and safety. This review describes the animal models used in pulmonary research for aerosol drug delivery, highlighting their advantages and limitations for inhaled biologics. Overall, non-clinical species must be selected with relevant scientific arguments while taking into account their complexities and interspecies differences, to help in the development of inhaled medicines and ensure their successful transposition in the clinics.

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“…These liabilities include chemical degradations such as oxidation, deamidation, isomerization, and fragmentation. [6][7][8][9][10] Deamidation of asparagine (Asn) residues is a major posttranslational modification that can significantly impact protein structure and function. 11,12 The non-enzymatic modification proceeds via formation of a five-member ring succinimide intermediate, which is subsequently hydrolyzed into a mixture of isoaspartate (isoAsp) and aspartate (Asp).…”

Section: Introductionmentioning

confidence: 99%

Engineering an anti-CD52 antibody for enhanced deamidation stability

Qiu¹,

Wei²,

Bird³

et al. 2019

mAbs

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Deamidation evaluation and mitigation is an important aspect of therapeutic antibody developability assessment. We investigated the structure and function of the Asn-Gly deamidation in a human anti-CD52 IgG1 antibody light chain complementarity-determining region 1, and risk mitigation through protein engineering. Antigen binding affinity was found to decrease about 400-fold when Asn33 was replaced with an Asp residue to mimic the deamidation product, suggesting significant impacts on antibody function. Other variants made at Asn33 (N33H, N33Q, N33H, N33R) were also found to result in significant loss of antigen binding affinity. The co-crystal structure of the antigen-binding fragment bound to a CD52 peptide mimetic was solved at 2.2Å (PDB code 6OBD), which revealed that Asn33 directly interacts with the CD52 phosphate group via a hydrogen bond. Gly34, but sits away from the binding interface, rendering it more amendable to mutagenesis without affecting affinity. Saturation mutants at Gly34 were prepared and subjected to forced deamidation by incubation at elevated pH and temperature. Three mutants (G34R, G34K and G34Q) showed increased resistance to deamidation by LC-MS peptide mapping, while maintaining high binding affinity to CD52 antigen measured by Biacore. A complement -dependent cytotoxicity assay indicated that these mutants function by triggering antibody effector function. This study illustrates the importance of structure-based design and extensive mutagenesis to mitigate antibody developability issues.

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Therapeutic monoclonal antibodies for respiratory diseases: Current challenges and perspectives, March 31 – April 1, 2016, Tours, France

Cited by 38 publications

References 62 publications

Production, characterization, andin vivohalf-life extension of polymeric IgA molecules in mice

Production, characterization, andin vivohalf-life extension of polymeric IgA molecules in mice

Insights on animal models to investigate inhalation therapy: Relevance for biotherapeutics

Engineering an anti-CD52 antibody for enhanced deamidation stability

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