Creating molecules that modulate immune responses

Kasteren, Sander I. van; Neefjes, Jacques; Ovaa, Huib

doi:10.1038/s41570-018-0023-9

Cited by 16 publications

(12 citation statements)

References 131 publications

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“…Monoclonal antibodies (mAbs) represent the largest class of biotherapeutics in the current pipeline of the pharmaceutical industry, as their high specificity and efficacy make them ideal candidates for treating high-impact illnesses such as various type of cancers 1 and autoimmune diseases. 2 Currently, more than 30 antibody or antibody-derived therapeutics are marketed worldwide, and a larger number of similar proteins are under development or going through clinical trials. 3,4 However, the success or failure of a given candidate is directly related to our ability to identify suitable formulations that provide long-term (1 year or longer) stability for these molecules.…”

Section: Introductionmentioning

confidence: 99%

Evaluating the Effects of Hinge Flexibility on the Solution Structure of Antibodies at Concentrated Conditions

Blanco

Hatch

Curtis

et al. 2019

Journal of Pharmaceutical Sciences

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Employing two different coarse-grained models, we evaluated the effect of intramolecular domaindomain distances and hinge flexibility on the general solution structure of antibodies (mAbs), within the context of protein-protein steric repulsion. These models explicitly account for the hinge region, and represent antibodies at either domain or subdomain levels (i.e., 4-bead and 7bead representations, respectively). Additionally, different levels of mAb flexibility are also considered. When evaluating mAbs as rigid structures, analysis of small-angle scattering (SAS) profiles showed that changes in the relative internal distances between Fc and Fab domains significantly alter the local arrangement of neighboring molecules, as well as the molecular packing of the concentrated mAb solutions. Likewise, enabling hinge flexibility in either of the mAb models led to qualitatively similar results, where flexibility increases the spatial molecular arrangement at elevated concentrations. This occurs because fluctuations in mAb quaternary structure are modulated by the close proximity between molecules at elevated concentrations (> 50 mg/mL), yielding an increased molecular packing and osmotic compressibility. However, our results also showed that the mechanism behind this synergy between flexibility and packing strongly depends on both the level of structural detail and the number of degrees of freedom considered in the coarse-grained model.

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Section: Introductionmentioning

confidence: 99%

Evaluating the Effects of Hinge Flexibility on the Solution Structure of Antibodies at Concentrated Conditions

Blanco

Hatch

Curtis

et al. 2019

Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

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“…The preparation of the target compound 7 (83%) was carried out from compound L-3 according to the general lev deprotection procedure, and it was obtained as a syrup. 1 (11). The preparation of the target compound 11 (75%) was carried out from compound 7 according to the general deprotection of esters procedure, and it was obtained as a sticky solid.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

“…4−10 Thus, the selective inhibition of chemokines can be beneficial in controlling inflammation, viral entry, and cancer progression. 11,12 Despite two decades of research in this area, only two antagonists for chemokine receptors have successfully passed clinical trials. 13−15 Hence, there is an urgent need for new approaches in controlling chemokine activity.…”

Section: ■ Introductionmentioning

confidence: 99%

Heparan Sulfate Mimetics Differentially Affect Homologous Chemokines and Attenuate Cancer Development

et al. 2021

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Achieving selective inhibition of chemokine activity by structurally well-defined heparan sulfate (HS) or HS mimetic molecules can provide important insights into their roles in individual physiological and pathological cellular processes. Here, we report a novel tailor-made HS mimetic, which furnishes an exclusive iduronic acid (IdoA) scaffold with different sulfation patterns and oligosaccharide chain lengths as potential ligands to target chemokines. Notably, highly sulfated-IdoA tetrasaccharide (I-45) exhibited strong binding to CCL2 chemokine thereby blocking CCL2/CCR2-mediated in vitro cancer cell invasion and metastasis. Taken together, IdoA-based HS mimetics offer an alternative HS substrate to generate selective and efficient inhibitors for chemokines and pave the way to a wide range of new therapeutic applications in cancer biology and immunology.

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“…Immunomodulators are a diverse array of natural, recombinant, and synthetic agents that act at different cellular and molecular levels of the immune system. By modulating immune response to a desired level, as in immunostimulants or immunosuppressants, immunotherapeutic agents provide an avenue for prophylactic or chronic disease control . Different types of therapeutics have been developed to activate or inhibit specific populations of immune cells and selectively target the signaling pathways engaged in immune regulation. − Recently, the field of tumor immunology has gained a tremendous amount of momentum owing to the success of novel cancer immunotherapies.…”

Section: Introductionmentioning

confidence: 99%

Covalent Small Molecule Immunomodulators Targeting the Protease Active Site

2021

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Cells of the immune system utilize multiple proteases to regulate cell functions and orchestrate innate and adaptive immune responses. Dysregulated protease activities are implicated in many immune-related disorders; thus, protease inhibitors have been actively investigated for pharmaceutical development. Although historically considered challenging with concerns about toxicity, compounds that covalently modify the protease active site represent an important class of agents, emerging not only as chemical probes but also as approved drugs. Here, we provide an overview of technologies useful for the study of proteases with the focus on recent advances in chemoproteomic methods and screening platforms. By highlighting covalent inhibitors that have been designed to target immunomodulatory proteases, we identify opportunities for the development of small molecule immunomodulators.

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Creating molecules that modulate immune responses

Cited by 16 publications

References 131 publications

Evaluating the Effects of Hinge Flexibility on the Solution Structure of Antibodies at Concentrated Conditions

Evaluating the Effects of Hinge Flexibility on the Solution Structure of Antibodies at Concentrated Conditions

Heparan Sulfate Mimetics Differentially Affect Homologous Chemokines and Attenuate Cancer Development

Covalent Small Molecule Immunomodulators Targeting the Protease Active Site

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