LAP: Liability Antibody Profiler by sequence & structural mapping of natural and therapeutic antibodies.

Antibody-based therapeutics must not undergo chemical modifications that would impair their efficacy or hinder their developability. A commonly used technique to de-risk lead biotherapeutic candidates annotates chemical liability motifs on their sequence. By analyzing sequences from all major sources of data (therapeutics, patents, GenBank, literature, and next-generation sequencing outputs), we find that almost all antibodies contain an average of 3-4 such liability motifs in their paratopes, irrespective of the source dataset. This is in line with the common wisdom that liability motif annotation is over-predictive. Therefore, we have compiled three computational flags to prioritize liability motifs for removal from lead drug candidates: 1. germline, to reflect naturally occurring motifs, 2. therapeutic, reflecting chemical liability motifs found in therapeutic antibodies, and 3. surface, indicative of structural accessibility for chemical modification. We show that these flags annotate approximately 60% of liability motifs as benign, that is, the flagged liabilities have a smaller probability of undergoing degradation as benchmarked on two experimental datasets covering deamidation, isomerization, and oxidation. We combined the liability detection and flags into a tool called Liability Antibody Profiler (LAP), publicly available at lap.naturalantibody.com. We anticipate that LAP will save time and effort in de-risking therapeutic molecules.

Benchmarking antibody clustering methods using sequence, structural, and machine learning similarity measures for antibody discovery applications.

Antibodies are proteins produced by our immune system that have been harnessed as biotherapeutics. The discovery of antibody-based therapeutics relies on analyzing large volumes of diverse sequences coming from phage display or animal immunizations. Identification of suitable therapeutic candidates is achieved by grouping the sequences by their similarity and subsequent selection of a diverse set of antibodies for further tests. Such groupings are typically created using sequence-similarity measures alone. Maximizing diversity in selected candidates is crucial to reducing the number of tests of molecules with near-identical properties. With the advances in structural modeling and machine learning, antibodies can now be grouped across other diversity dimensions, such as predicted paratopes or three-dimensional structures. Here we benchmarked antibody grouping methods using clonotype, sequence, paratope prediction, structure prediction, and embedding information. The results were benchmarked on two tasks: binder detection and epitope mapping. We demonstrate that on binder detection no method appears to outperform the others, while on epitope mapping, clonotype, paratope, and embedding clusterings are top performers. Most importantly, all the methods propose orthogonal groupings, offering more diverse pools of candidates when using multiple methods than any single method alone. To facilitate exploring the diversity of antibodies using different methods, we have created an online tool-CLAP-available at (clap.naturalantibody.com) that allows users to group, contrast, and visualize antibodies using the different grouping methods.