Computational Antibody Papers

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  • 2024-02-26

    Assessing developability early in the discovery process for novel biologics

    • developability
    • Review on developability methods, very good reference for what are the problems afflicting antibodies, what assays are used and it gives perspective where computational might have an impact.
    • Specific binding high on-target binding and low off-target and non-specific binding is important to reduce the risks of abnormal pharmacokinetics and fast antibody clearance.
    • Polyspecificity. For nonspecific binding ELISA can be used to check non-specific binding for non-targets. Polyspecificify particle assay (PSP) checks binding to complex antigen mixtures. Polyspecificity reagent (PSR) is similar to PSP. In Cross interaction Chromatography (CIC) non-specific protein interactions, such as monoclonal antibodies interacting with immobilized polyclonal antibodies, are detected via their relative retention times. Standup monolayer chromatography (SMAC), instead detects non-specific interactions between monoclonal antibodies and the column.
    • Colloidal stability, self-association. Self interaction Chromatography (SIC). AC-SINS, affinity-capture self-interaction nanoparticle spectroscopy and charge-stabilized self-interaction nanoparticle spectroscopy (CS-SINS). Also HIC.
    • Folding stability. Differential scanning calorimetry or differential scanning fluorimetry.
    • Ideally antibodies would have a shelf-life of several years which requires stability engineering.
    • Assays can be performed in formulation (pH 6, 10 mM histidine) or physiological conditions (pH 7.4, phosphate-buffered saline).
    • Generally, the isoelectric point of therapeutic antibodies is between 6 and 9. However, various developability challenges have been reported for some antibodies with relatively low (pI <6.5-7) or high (pI >8.5-9) isoelectric points
    • Computational assays can include: naturalness prediction, MHC class II, ptm liabilities, isoelectric point (pI), charge, hydrophobic imbalance, surface areas buried at the VH-VL interface along with molecular surface patches
    • Antibodies are flexible & crystallization might not reflect well the actual dominant structure adopted.
    • T-cell epitope assay: This may be addressed in vitro by the use of immune cell activation assays, where pooled peripheral blood mononuclear cells are exposed to candidate biologics to reveal the presence of activating T cell epitopes.
    • Antibodies have quite a long half-life (3 weeks) because they can engage the FcRn receptor which rescues the ligands from cellular recycling. The efficiency by which different biologics undergo this process has an enormous impact on their pharmacokinetic properties and biodistribution
    • There are some raging differences between humans and mice for the animal to be used as a model organism:
    • While being a potent vascular endothelial growth factor (VEGF)-blocker in humans, the widely used anti-VEGF human IgG1 bevacizumab is unable to block mouse VEGF, implying that mice could not have been used in its development.
    • Our understanding of FcRn biology has revealed major differences that must be taken into consideration when conventional mice are used. This is due to large differences in ligand binding to mouse and human FcRn, where mouse IgG binds very weakly to the human form, and human IgG binds stronger to mouse FcRn than to the human counterpart.
    • Most antibodies are IV, but there are some experiments with abs targeting infections in the GI tract and these are oral.

  • 2023-04-29

    AbNatiV: VQ-VAE-based assessment of antibody and nanobody nativeness for engineering, selection, and computational design

    • humanization
    • immunogenicity
    • Creating a nativeness score for humans and VHHs using a variant of variational auto-encoder (VAE).
    • They used approximately 2m sequences for heavy, kappa, lambda and nanobody each.
    • Model is VQ-VAE trained on masked language modeling objective with VAE-specific terms incorporated in the loss function.
    • The nativeness definition is a transformation of the |x_r - x_n|, that is the MSE of the original and reconstructed sequence.
    • They used the data from the ‘universal Nb framework’ paper to perform VHH grafting experiments.
    • They tested against other methods whether they could predict human vs non-human sequence (humanized, chimeric, mouse), they are the best with pr AUC of 975. Closest was Oasis and Germline content with pr AUC of .963
    • ADA on 126 therapeutics shows r2 of .25.
    • As a nanobody humanization case-study they employed antibodies from another paper that offer WT and humanized variants. They show that their score moves the humanized variants closer to the human distribution - but human and VHH humannesses are still far separated.
    • When they have species-matched predictions, they call it nativeness. If they score VHH on human models, they call it humanness.