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  • 1
    Online Resource
    Online Resource
    The promise of machine learning: using Seismic’s IMPACT platform to design IgG cleaving enzymes for chronic treatment of autoimmune diseases
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 210, No. 1_Supplement ( 2023-05-01), p. 238.22-238.22
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 1_Supplement ( 2023-05-01), p. 238.22-238.22
    Abstract: Proteases derived from human pathogens can specifically cleave IgG into F(ab′)2 and Fc fragments. This unique trait suggests a novel opportunity to use these molecules to treat auto antibody mediated disease. IdeS, an IgG cleaving enzyme derived from Streptococcus pyogenes has shown clinical proof of concept and is approved for use before kidney transplant. Due to the immunogenic nature of these proteases, the dosing regimen is impacted by pre-existing antibodies and the induction of anti-drug antibodies after dosing. To mitigate the impact of the immune system on our novel enzyme, we employed our IMPACT platform leveraging machine learning to reduce T and B cell epitopes and to ensure that our molecule exhibits desirable drug like properties while maintaining enzymatic activity. To extend the pharmacokinetics (PK) of our molecule, we fused it with a Fc domain. To evaluate IgG protease PK and pharmacodynamics (PD), intravenous immunoglobulin (IVIg) was injected at different time points after protease treatment and IgG levels were quantified by MSD. As expected, the addition of the Fc increased the molecule’s half-life that resulted in a PD effect at later time points than observed with a control enzyme without a Fc. Taken together, our IMPACT platform leveraging machine learning demonstrates that we can optimize drug-like properties and reduce the immunogenicity of a molecule while maintaining function, resulting in a potential novel treatment for chronic autoimmune diseases.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.210.Supp.238_22
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    The promise of machine learning: using Seismic’s IMPACT platform to design IgG cleaving enzymes for chronic treatment of autoimmune diseases
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 210, No. 1_Supplement ( 2023-05-01), p. 85.13-85.13
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 1_Supplement ( 2023-05-01), p. 85.13-85.13
    Abstract: Proteases derived from human pathogens can specifically cleave IgG into F(ab′)2 and Fc fragments. This unique trait suggests a novel opportunity to use these molecules to treat auto antibody mediated disease. IdeS, an IgG cleaving enzyme derived from Streptococcus pyogenes has shown clinical proof of concept and is approved for use before kidney transplant. Due to the immunogenic nature of these proteases, the dosing regimen is impacted by pre-existing antibodies and the induction of anti-drug antibodies after dosing. To mitigate the impact of the immune system on our novel enzyme, we employed our IMPACT platform leveraging machine learning to reduce T and B cell epitopes and to ensure that our molecule exhibits desirable drug like properties while maintaining enzymatic activity. To extend the pharmacokinetics (PK) of our molecule, we fused it with a Fc domain. To evaluate IgG protease PK and pharmacodynamics (PD), intravenous immunoglobulin (IVIg) was injected at different time points after protease treatment and IgG levels were quantified by MSD. As expected, the addition of the Fc increased the molecule’s half-life that resulted in a PD effect at later time points than observed with a control enzyme without a Fc. Taken together, our IMPACT platform leveraging machine learning demonstrates that we can optimize drug-like properties and reduce the immunogenicity of a molecule while maintaining function, resulting in a potential novel treatment for chronic autoimmune diseases.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.210.Supp.85.13
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    High-throughput Western Blot for in vitro and in vivo assessment of human Ig specific cleaving enzymes
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 210, No. 1_Supplement ( 2023-05-01), p. 238.19-238.19
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 1_Supplement ( 2023-05-01), p. 238.19-238.19
    Abstract: Antibodies play a vital role in the body’s immune defense mechanism. However, pathogenic Ig antibodies are thought to contribute to several autoimmune conditions and transplant rejection. Proteases derived from human pathogens can specifically cleave IgG into F(ab’)2 and Fc fragments, thus allowing for rapid clearance of IgG. This unique trait suggests a novel opportunity to use these molecules to treat autoantibody mediated diseases. Using our IMPACT platform leveraging machine learning, we have engineered Ig proteases that specifically cleave IgG, and treatment with these proteases causes cleavage below the hinge region, which can result in the generation of the following degradation products: 1) Fab’2 and Fc fragments lacking effector function; or 2) single chain cleaved fragments with reduced effector functions. To detect these species, we developed a method using JESS, an automated high throughput western blot instrument. Using this system, we can detect intact, single cleaved and fully cleaved IgG in a time and dose dependent manner in both in vitro and in vivo assays. In conclusion, we successfully optimized a high throughput assay format that is highly specific and sensitive in evaluating the cleavage activity of different Ig proteases and could be a powerful tool to assess efficacy of IgG cleaving enzymes in the clinic.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.210.Supp.238.19
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 4
    Online Resource
    Online Resource
    Identifying next generation Ig selective cleaving enzymes for treatment of autoimmune diseases using IMPACT platform
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 210, No. 1_Supplement ( 2023-05-01), p. 246.06-246.06
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 1_Supplement ( 2023-05-01), p. 246.06-246.06
    Abstract: Dysregulated humoral immune mechanisms result in immunoglobulin production that is pathogenic and contributes to a wide range of autoimmune diseases and transplant rejection. Proteases derived from human pathogens can specifically cleave these immunoglobulins (Ig) and can potentially eliminate circulating, cell-surface and immune-complex Ig classes and modulate Ig-mediated autoimmunity and inflammation, providing a novel opportunity to treat antibody-mediated diseases. We describe here the discovery, generation, and functional characterization of Ig specific proteases. These proteases were identified using Seismic Therapeutic’s IMPACT platform and tested for their ability to cleave intact Ig subclasses and Ig isotypes in a high-throughput CE-SDS cleavage assay. Additionally, we found that these enzymes cleave soluble and cell bound Ig in human blood, dramatically reducing effector function. We believe that these subclass and isotype specific cleaving proteases will provide an opportunity to develop novel targeted therapies for various autoimmune diseases where autoantibodies are the key drivers of the disease. In addition, we believe that they will be potentially better tolerated compared to current therapeutic interventions such as plasma exchange and other immunosuppressive therapies.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.210.Supp.246.06
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
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