The present disclosure provides novel macrocyclic peptides which inhibit the PD-1/PD-L1 and PD-L1/CD80 protein/protein interaction, and thus are useful for the amelioration of various diseases, including cancer and infectious diseases.

Provided is a method for preparing a PD-1 gene-modified humanized animal model. The method utilizes the CRIPSR/Cas9 technique to replace partial fragments of a mouse PD-1 gene with fragments of a human PD-1 gene using homologous recombination by constructing a targeting vector, thereby preparing a gene-modified humanized mouse. This mouse can normally express a PD-1 protein containing the functional domain of the human PD-1 protein, and can be used as an animal model for mechanism research regarding PD-1, PD-L1 and other signals, for screening regulators, and for toxicological research. The method has an important and high application value in studies on functions of the PD-1 gene and in the development of new drugs.

Provided herein are novel .sup.10Fn3 domains which specifically bind to PD-L1, as well as imaging agents based on the same for diagnostics.

This document provides materials and methods for treating cancer (e.g., PD-L1.sup.+ cancers). For example, methods and materials for using compositions (e.g., compositions containing a small bioactive S249/T252 phospho-mimicking polypeptide of an RB polypeptide) to reduce PD-L1 expression within cancer cells are provided. In addition, methods and materials for using compositions (e.g., compositions containing a small bioactive S249/T252 phospho-mimicking polypeptide of an RB polypeptide) in combination with other cancer treatment methods or agents to increase the effectiveness exhibited against the cancer within a mammal (e.g., a human) are provided.

The disclosure relates to the field of immuno-oncology. More specifically, the disclosure relates to methods and compositions for performing single-cell phenotypic and functional analysis of immune and cancer cells disposed within a tumor microenvironment. The methods and compositions permit the determination of whether a subject with a solid tumor is likely to respond to a particular immunomodulator, and also permit the treatment of a solid tumor in a subject by facilitating the selection of an immunomodulator suitable for treating the solid tumor in the subject.

The present invention provides an anti-B7-H3 monoclonal antibody and use thereof in cell therapy. Specifically, the present invention provides an scFv, an antibody, and a specific CAR-T cell specifically targeting B7-H3. The present invention further provides an engineered immune cell capable of co-expressing a CAR targeting B7-H3 and a chimeric molecule or a secreted protein of PD-L1, the engineered immune cell having good tumor killing effects.

The present disclosure relates generally to the analysis of immune checkpoint proteins involved in cancer. In particular, the present disclosure provides material and methods for determining abundance ratios of various immune checkpoint proteins (e.g., PD-1, PD-L1, and PD-L2) present in a biospecimen sample based on quantification of peak area using mass spectrometry analysis. The methods disclosed herein provide an alternative platform for diagnosing and treating cancer, especially in cases limited by ineffective antibody recognition.

Disclosed herein are antibodies that bind to PD-1, comprising one or more CDRs selected from the amino acid sequences of SEQ ID NOs: 13, 14, 15, 16, 17, and 18. The antibodies have high affinity and low dissociation rate for PD-1, as well as the activity for neutralizing PD-1 in vitro. The antibodies disclosed herein can be full-length antibodies or antigen-binding fragments thereof. The antibodies can be used for detecting PD-1 and the like.

Provided is a bispecific fusion protein having a novel structure. A second binding structural domain is inserted into an IgG hinged region in a full length by means of an optional peptide joint. The fusion protein has the same expression and production advantages as those of IgG, does not influence the binding activity of an Fab region of the fusion protein and further improves the stability and obtains a higher half life. In addition, the binding activity of the second binding structural domain to a target binding site is significantly improved with respect to the binding activity of a monomer corresponding to a soluble natural binding fragment to a corresponding target.

The present disclosure relates to PD-L1-binding molecules comprising a Shiga toxin effector region, a PD-L1-binding region, and a T cell epitope, and pharmaceutical compositions thereof. The PD-L1 binding molecules and pharmaceutical compositions thereof have uses for selectively killing specific cells (e.g., PD-L1 positive tumor cells and/or immune cells), for selectively delivering cargos to specific cells (e.g., PD-L1 positive tumor cells or immune cells), and as therapeutics for treating or slowing the progression of cancer (e.g., non-small cell lung cancer or squamous cell carcinoma of the head and neck). The present disclosure also relates to clinical methods for use of the disclosed PD-L1 binding molecules for treating a subject in need thereof.