Therapeutic interferon alpha 1 proteins

A chimeric protein complex comprising:

• (a) a human interferon alpha 1 (IFNα1) comprising an amino acid sequence having at least 98% identity with SEQ ID NO:
• 1 and having a substitution selected from C86S, C86A, and C86Y,
• (b) a targeting moiety comprising a recombinant heavy-chain-only antibody (VHH) that specifically binds to a cellular target selected from Cluster of differentiation 20 (CD20), C-type lectin domain containing 9A (Clec9A), and Programmed death-ligand 1 (PD-L1), or a targeting moiety comprising FMS-like tyrosine kinase 3 ligand (Flt3L);
• wherein:
• the IFNα1 of the chimeric protein complex exhibits attenuated activity as compared to wild type IFNα1 having SEQ ID NO:
• 1;
• and
• (c) an Fc domain connecting the IFNα1 and the one or more targeting moieties, the Fc domain having one or more mutations that reduce or eliminate one or more effector functions of the Fc domain, promotes Fc chain pairing in the Fc domain, or stabilizes a hinge region in the Fc domain, and being derived from a human IgG, selected from human IgG1, IgG2, IgG3, and IgG4,
• wherein the chimeric protein complex is a heterodimer having a trans orientation/configuration, as relates to any targeting moiety and IFNα1, relative to each other.