The present application relates to immunomodulatory molecules comprising a first
binding domain (e.g., an immunostimulatory
cytokine, such as IL-2 or IL-12, or a variant thereof) that specifically recognizes a first target molecule (e.g., a
receptor for an immunostimulatory
cytokine) and a second
binding domain (e.g., an
agonist ligand, such as PD-L1 or PD-L2, or a variant thereof, or an
agonist antigen-binding fragment, such as an anti-PD-1
agonist Fab, scFv, VHH, or full length
antibody) that specifically recognizes a second target molecule (e.g., an inhibitory checkpoint molecule, such as PD-1), wherein the first
binding domain, upon binding to the first target molecule, upregulates an immune response and the second binding domain, upon binding to the second target molecule, downregulates an immune response. Methods of making and using such immunomodulatory molecules are also provided.