Genetically programmed microorganisms, such as bacteria or virus, pharmaceutical compositions thereof, and methods of modulating and treating cancers are disclosed.

PD1-41BBL fusion proteins are provided. Accordingly, there is provided a PD1-41BBL fusion protein comprising a single amino acid linker between the PD1 and the 41BBL. Also there is provided a PD1-41BBL fusion protein, wherein the PD1 amino acid is 123-166 amino acids in length and/or wherein the PD1 amino acid sequence comprises SEQ ID NO: 2 and/or wherein the fusion protein is in a form of at least a homo-trimer. Also provided are polynucleotides and nucleic acid constructs encoding the PD1-41BBL fusion protein, host-cells expressing the PD1-41BBL fusion protein and methods of use thereof.

The present invention relates to multimers of polypeptides which are covalently bound to molecular scaffolds such that two or more peptide loops are subtended between attachment points to the scaffold. The invention also describes the multimerization of polypeptides through various chemical linkers and hinges of various lengths and rigidity using different sites of attachments within polypeptides. In particular, the invention describes multimers of peptides which are high affinity binders and activators of CD137. The invention also includes drug conjugates comprising said peptides, conjugated to one or more effector and/or functional groups, to pharmaceutical compositions comprising said peptide ligands and drug conjugates and to the use of said peptide ligands and drug conjugates in preventing, suppressing or treating a disease or disorder mediated by CD137.

PD1-CD70 fusion proteins are provided. Accordingly, there is provided a PD1-CD70 fusion protein comprising a single amino acid linker between the PD1 and the CD70. Also there is provided a PD1-CD70 fusion protein, wherein the PD1 amino acid is 123-166 amino acids in length and/or wherein the PD1 amino acid sequence comprises SEQ ID NO: 2 and/or wherein the fusion protein is in a form of at least a homo-trimer. Also provided are polynucleotides and nucleic acid constructs encoding the PD1-CD70 fusion protein, host-cells expressing the PD1-CD70 fusion protein and methods of use thereof.

Provided in the present invention are a 4-1BB antibody and a preparation method and the use thereof. In particular, provided in the present invention are a 4-1BB antibody, which has high affinity to 4-1BB protein, can effectively activate the signal downstream of the 4-1BB and significantly increase expression quantities of IFN-γ and IL-2 in human mixed lymphocytes or T lymphocytes, and can be used to treat cancers and autoimmune diseases.

The invention relates to the field of immunology and immuno-oncology. More specifically, the invention relates to multi-specific and bi-specific cytokine and antibody derivatives capable of cell and/or tissue targeting to locally enhance the immune response and to reduce systemic toxicity.

Embodiments of the disclosure include methods and compositions for inhibiting the immune suppressive tumor microenvironment using cell therapy wherein the cells express a chimeric protein having an extracellular domain that binds TRAIL-R2 and an intracellular domain that in specific embodiments comprises one or more costimulatory domains that enhance activity of the cells upon activation. In specific embodiments, the chimeric protein comprises an scFv that targets TRAIL-R2 and an intracellular region that comprises a costimulatory domain from 4-1BB. In particular embodiments, the cells also express a therapeutic protein, such as a chimeric antigen receptor.

The present disclosure relates to, inter alia, a method for treating a tumor by intratumorally delivering an effective amount of a composition comprising an expression vector that comprises a first nucleotide sequence encoding a secretable vaccine protein, and a second nucleotide sequence encoding a T cell costimulatory fusion protein.

The present disclosure provides T-cell modulatory multimeric polypeptides (T-Cell-MMP) and their epitope conjugates comprising at least one immunomodulatory polypeptide (“MOD”) that may be selected to exhibit reduced binding affinity to a cognate co-immunomodulatory polypeptide (“Co-MOD”). The epitope may be, for example, a cancer-associated epitope, an infectious disease-associated epitope, or a self-epitope. The T-Cell-MMP-epitope conjugates are useful for modulating the activity of a T-cell by delivering immunomodulatory peptides, such as IL-2 or IL-2 variants that exhibit reduced binding affinity for the IL-2R, to T-cells in an epitope selective/specific manner, and accordingly, for treating individuals with a cancer, infectious disease or autoimmune disorder.

The present invention relates to multimers of polypeptides which are covalently bound to molecular scaffolds such that two or more peptide loops are subtended between attachment points to the scaffold. The invention also describes the multimerization of polypeptides through various chemical linkers and hinges of various lengths and rigidity using different sites of attachments within polypeptides. In particular, the invention describes multimers of peptides which are high affinity binders and activators of CD137. The invention also includes drug conjugates comprising said peptides, conjugated to one or more effector and/or functional groups, to pharmaceutical compositions comprising said peptide ligands and drug conjugates and to the use of said peptide ligands and drug conjugates in preventing, suppressing or treating a disease or disorder mediated by CD137.