Discovery and multi-parametric optimization of a high-affinity antibody against interleukin-25 with neutralizing activity in a mouse model of skin inflammation

Bone, Ruth E.; Fennell, Brian J.; Tam, Amy; Sheldon, Richard; Nocka, Karl; Varghese, Sreeja; Chang, Chew Shun; Hawerkamp, Heike C.; Yeow, Aoife; Saunders, Sean P.; Hams, Emily; Walsh, Patrick; Cunningham, Orla; Fallon, Padraic G.

doi:10.1093/abt/tbac022

Cited by 2 publications

(1 citation statement)

References 22 publications

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“…As described above, a number of retrospective and prospective studies have provided additional validation of the ISPRI platform for monospecific and bispecific mAbs. 21 , 23 , 24 , 34 , 74 , 92 Recent publications on immunogenicity risk assessment can provide additional detail. 30 , 93 Other clinically relevant factors such as dose and frequency of administration, route of administration, concomitant medications, and the mechanism of action, and other product-related considerations, including formulation (for example, the presence of innate immune response modifiers in the formulated drug product that may act as immunostimulatory adjuvants), aggregation, oxidation, deamidation, and other chemical degradative processes, may modify the immunogenic potential of biologic therapeutics.…”

Section: Discussionmentioning

confidence: 99%

In silico methods for immunogenicity risk assessment and human homology screening for therapeutic antibodies

Mattei,

Gutierrez,

Seshadri

et al. 2024

mAbs

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In silico immunogenicity risk assessment has been an important step in the development path for many biologic therapeutics, including monoclonal antibodies. Even if the source of a given biologic is ‘fully human’, T cell epitopes that are contained in the sequences of the biologic may activate the immune system, enabling the development of anti-drug antibodies that can reduce drug efficacy and may contribute to adverse events. Computational tools that identify T cell epitopes from primary amino acid sequences have been used to assess the immunogenic potential of therapeutic candidates for several decades. To facilitate larger scale analyses and accelerate preclinical immunogenicity risk assessment, our group developed an integrated web-based platform called ISPRI, (Immunogenicity Screening and Protein Re-engineering Interface) that provides hands-on access through a secure web-based interface for scientists working in large and mid-sized biotech companies in the US, Europe, and Japan. This toolkit has evolved and now contains an array of algorithms that can be used individually and/or consecutively for immunogenicity assessment and protein engineering. Most analyses start with the advanced epitope mapping tool (EpiMatrix), then proceed to identify epitope clusters using ClustiMer, and then use a tool called JanusMatrix to define whether any of the T cell epitope clusters may generate a regulatory T cell response which may diminish or eliminate anti-drug antibody formation. Candidates can be compared to similar products on a normalized immunogenicity scale. Should modifications to the biologic sequence be an option, a tool for moderating putative immunogenicity by editing T cell epitopes out of the sequence is available (OptiMatrix). Although this perspective discusses the in-silico immunogenicity risk assessment for monoclonal antibodies, bi-specifics, multi-specifics, and antibody-drug conjugates, the analysis of additional therapeutic modalities such as enzyme replacement proteins, blood factor proteins, CAR-T, gene therapy products, and peptide drugs is also made available on the ISPRI platform.

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Section: Discussionmentioning

confidence: 99%

In silico methods for immunogenicity risk assessment and human homology screening for therapeutic antibodies

Mattei,

Gutierrez,

Seshadri

et al. 2024

mAbs

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Does human homology reduce the potential immunogenicity of non-antibody scaffolds?

De Groot,

Khan,

Mattei

et al. 2023

Front. Immunol.

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Biologics developers are moving beyond antibodies for delivery of a wide range of therapeutic interventions. These non-antibody modalities are often based on ‘natural’ protein scaffolds that are modified to deliver bioactive sequences. Both human-derived and non-human-sourced scaffold proteins have been developed. New types of “non-antibody” scaffolds are still being discovered, as they offer attractive alternatives to monoclonals due to their smaller size, improved stability, and ease of synthesis. They are believed to have low immunogenic potential. However, while several human-sourced protein scaffolds have not been immunogenic in clinical studies, this may not predict their overall performance in other therapeutic applications. A preliminary evaluation of their potential for immunogenicity is warranted. Immunogenicity risk potential has been clearly linked to the presence of T “helper” epitopes in the sequence of biologic therapeutics. In addition, tolerogenic epitopes are present in some human proteins and may decrease their immunogenic potential. While the detailed sequences of many non-antibody scaffold therapeutic candidates remain unpublished, their backbone sequences are available for review and analysis. We assessed 12 example non-antibody scaffold backbone sequences using our epitope-mapping tools (EpiMatrix) for this perspective. Based on EpiMatrix scoring, their HLA DRB1-restricted T cell epitope content appears to be lower than the average protein, and sequences that may act as tolerogenic epitopes are present in selected human-derived scaffolds. Assessing the potential immunogenicity of scaffold proteins regarding self and non-self T cell epitopes may be of use for drug developers and clinicians, as these exciting new non-antibody molecules begin to emerge from the preclinical pipeline into clinical use.

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Discovery and multi-parametric optimization of a high-affinity antibody against interleukin-25 with neutralizing activity in a mouse model of skin inflammation

Cited by 2 publications

References 22 publications

In silico methods for immunogenicity risk assessment and human homology screening for therapeutic antibodies

In silico methods for immunogenicity risk assessment and human homology screening for therapeutic antibodies

Does human homology reduce the potential immunogenicity of non-antibody scaffolds?

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