The invention is in the field of TNF signalling. Compounds have been identified which are capable of modulating signalling of TNF trimers through receptors. Methods of identifying such compounds are therefore provided. The compounds themselves have utility in therapy.

Provided herein are methods for identifying pairs of protein binding partners, mutations of which may inform the discovery of pharmaceutically useful small molecules. The methods disclosed herein may allow for the adaptation of the native protein degradation system to modulate specific disease targets at the protein level, in particular, for targets that have long been considered undruggable.

A method for synthesizing a synthetic molecule includes selecting a target protein, selecting a common precursor, providing first and second side-chains, forming a first monomer, including the common precursor and first side-chain, forming a second monomer, including the common precursor and second side-chain, evaluating the first and second monomers using an aggregation assay with the target protein to generate first results, and selecting one of the first and second monomers as a selected monomer based on the first results. Further, the method includes providing third and fourth monomers compatible with the selected monomer, forming a first dimer, including the selected monomer and third monomer, forming a second dimer, including the selected monomer and fourth monomer, evaluating the first and second dimers with the aggregation assay to generate second results, and selecting one of the first and second dimers as a selected dimer based on the second results.

Described here are VHH antibody libraries with heavy chain variable domains framework scaffolds having complementary determining regions (CDRs) found in naturally-occurring human antibodies, and methods of making such antibody libraries. The antibody libraries are free of members that comprise one or more liabilities affecting one or more features of such members.

A method for designing a chimeric antigen receptor (CAR), comprising: a) defining a training set of CAR sequences wherein each training CAR is associated with one or more properties; b) defining one or more objectives, each of the one or more objectives defining a desired property of a CAR; c) training a computational model using the training set of the one or more training CAR sequences to provide a trained computational model; d) using the computational model to provide at least one output CAR sequence, and wherein the at least one output CAR sequence is determined based on the one or more objectives. Methods of training a computational model for designing a chimeric antigen receptor (CAR), the trained model provided by such method, along with a CAR sequence output, the CAR encoded by the output CAR sequence and a cell expressing said CAR are also provided.

Provided are a peptide consisting of three complementarity determining regions and four framework regions, in which a framework 1 comprises an amino acid sequence represented by SEQ ID NO: 1, a framework 2 comprises an amino acid sequence represented by SEQ ID NO: 2, a framework 3 comprises an amino acid sequence represented by SEQ ID NO: 7, a framework 4 comprises an amino acid sequence represented by SEQ ID NO: 32, a complementarity determining region 1 is an amino acid sequence consisting of 10 amino acids, a complementarity determining region 2 is an amino acid sequence consisting of 16 or 17 amino acids, and a complementarity determining region 3 is an amino acid sequence consisting of 6, 12 or 15 amino acids; and a peptide library including the peptide.

The present invention provides compositions and methods that can be used to determine a peptide signature for an antibody repertoire in a sample comprising multiple antibodies. The method can be used to characterize a phenotype in a sample, such as providing a diagnosis, prognosis or theranosis of a medical condition.

Systems and methods for obtaining qualitative or quantitative measurements of proteoforms of polypeptides are described. The described methods include measurements of affinity reagent binding on single-molecule polypeptide arrays to distinguish between polypeptide isoforms. The described methods may provide high resolution quantitative comparisons of proteoforms with very low copy numbers.

Methods and systems for delivery using one or more delivery particles (e.g., virions (e.g., AAV), lipid-based delivery particles, etc.) of one or more cargos (e.g., cargo polypeptides) and subsequent quantification of an abundance of one or more cargos (e.g., proteins) in a mixture (e.g., a complex mixture (e.g., in vivo)) using barcodes (e.g., peptide barcodes), binders (e.g., polypeptide binders), and binding agents (e.g., phage) are provided herein.

Provided herein are compositions and methods for the identification of an expression profile in a single cell or population of cells. Kits for use with the disclosed methods are also provided, including antibodies, with a unique molecular identifier and antibody identifier, and primers for amplification of the antibody identifier sequence.