The present disclosure relates generally to compositions and methods for modulating signal transduction mediated by interleukin-12 and interleukin-23. In particular, the disclosure provides novel variants of interleukin-12 subunit p40 with reduced binding affinity to IL-12Rβ1. Also provided are compositions and methods useful for producing such IL-12p40 polypeptide variants, as well as methods for modulating IL-12p40-mediated signaling, and/or for the treatment of conditions associated with perturbations of signal transduction mediated by IL-12p40.

The present invention provides, in certain aspects, a natural killer (NK) cell that expresses all or a functional portion of interleukin-15 (IL-15), and methods for producing such cells. The invention further provides methods of using a natural killer (NK) cell that expresses all or a functional portion of interleukin-15 (IL-15) to treat cancer in a subject or to enhance expansion and/or survival of NK cells.

The present invention is directed to novel bispecific heterodimeric Fc fusion proteins comprising an IL-15/IL-15Rα Fc-fusion protein and a PD-1 antibody fragment-Fc fusion protein.

Modified alphaviruses encoding a SARS-CoV-2 spike protein or antigenic segment of the SARS-CoV-2 spike protein are provided. The modified alphaviruses include replicative defective Sindbis viruses. The modified viruses express or are administered with an immunomodulatory agent that is an agonist antibody or antigenbinding fragment thereof, or a cytokine, or a combination thereof. Pharmaceutical compositions that include the modified alphaviruses and methods of using the modified alphaviruses and compositions that contain them are provided. The compositions are used to stimulate a therapeutic or protective effect against SARS-CoV-2 infection that includes humoral and cell mediated responses.

A method of creating antigen-specific, chimeric antigen receptor (CAR) T cells capable of secreting regenerative growth factors upon activation of said CAR. In one embodiment said regenerative CAR-T cells possess a CAR capable of selectively recognizing damaged tissue. In one embodiment said CAR recognizes damage-associated molecular patterns (DAMPs) such as ATP, HMGB-1, matricryptins, cold-inducible RNA-binding protein, histones and mitochondrial DNA. Upon activation of said CAR said regenerative CAR-T cell is induced to produce one or more regenerative growth factors. In some embodiments the invention provides a suicide gene in said regenerative CAR-T cells in order to remove said cells after their therapeutic purpose is completed.

This invention provides a tetrahedral antibody comprising a first, second, third, and fourth domain, wherein each of the first and second domains are selected from the group consisting of a Fab domain and an Fc domain, wherein each of the first and second domains comprise a first polypeptide chain comprising a first N-terminus and a first C-terminus of the domain, and a second polypeptide chain comprising a second N-terminus and a second C-terminus of the domain, and wherein the first domain and the second domain are joined to each other by a non-peptidyl linkage between the first N-terminus of the first domain and the first N-terminus of the second domain, between first C-terminus of the first domain and the first C-terminus of the second domain, between the first N-terminus of the first domain and the first C-terminus of the second domain, or between the first C-terminus of the first domain and the first N-terminus of the second domain.

Provided herein is a construct comprising, in combination: an EphA3, EphA2 and/or EphB2 binding ligand; and at least one effector molecule. In some embodiments, the at least one effector molecule comprises a therapeutic agent, a nanoparticle, a detectable group, a lipid, or a liposome. In some embodiments, the construct is a fusion protein and/or a covalent conjugate. Further provided is a construct comprising, in combination: a ligand that binds to EphA2, EphA3 and/or EphB2; a ligand that binds to IL-13Rα2; and at least one effector molecule. Also provided are methods of use thereof for treating cancer.

The disclosure provides modified NK cells and pharmaceutical compositions comrpsing the same. The disclosure also provides methods of treating cancer using the same.

The disclosure provides modified NK cells and pharmaceutical compositions comrpsing the same. The disclosure also provides methods of treating cancer using the same.

An object is to elucidate the immune response mechanism of IL-17-producing cells which causes a pathological condition such as psoriasis, and to provide an immune response suppressant for suppressing the immune response of IL-17-producing cells, a medicament for treating or preventing a disease or a pathological condition involving the immune response of an IL-17-producing cell, a method for inducing immune response in γδT cells, and a method for evaluating a medicament (candidate substance) and a method for producing IL-17 by use of the method. The present invention provides an immune response suppressant for an IL-17-producing cell, including a substance that inhibits the binding of CD96 to at least one protein selected from CD155 and CD111, a medicament including the immune response suppressant for an IL-17-producing cell, a method having a step (A) of culturing at least one of a γδT cell and a CD4-positive T cell together with IL-23, an anti-CD3 antibody capable of stimulating a TCR/CD3 complex and an anti-CD96 antibody capable of stimulating CD96, and a method for evaluating a medicament (candidate substance) and a method for producing IL-17, including a method having the step (A).