The disclosure provides a multi-specific polypeptide with a first moiety specific for a tumor-associated antigen on tumor cell surface and a second moiety specific for an immune checkpoint protein, which multi-specific polypeptide can be useful for biasing a T-cell-mediated response to a tumor micro-environment. For example, the polypeptide may contain: a) a first binding domain, for example, a full-length antibody or an antigen-binding domain of an antibody, specifically recognizing a tumor-associated antigen on tumor cell surface, and b) a second binding domain, such as a lipocalin mutein, capable of stimulating T-cell proliferation e.g., by inhibiting a protein receptor that down-regulates the immune system. The first binding domain may be genetically linked (i.e., peptide bond at its N- or C-terminus) to the second binding domain. The multispecific polypeptide also may contain a third or yet additional specific binding moieties, any of which can specifically bind a distinct immune checkpoint protein. The polypeptide may contain an Fc region of an antibody or of an antigen-binding domain thereof and simultaneously engage (1) a T cell receptor complex of a T cell, (2) a tumor-associated antigen on tumor cell surface, while (3) preserving the Fc function of the Fc region to Fc receptor-positive cell. The polypeptide is useful for the induction of an anti-tumor immunity in humans and/or animals. The disclosure also provides thermal-stable lipocalin muteins specific for CTLA-4. The disclosure further relates to a process for the production of the polypeptide or muteins as well nucleic acids encoding for the polypeptide or muteins, to vectors comprising the same and to host cells comprising the vector. In another aspect, the disclosure provides for a pharmaceutical composition comprising the polypeptide or muteins and medical uses of the polypeptide or muteins.L'invention concerne un polypeptide multi-spécifique comportant une première fraction spécifique d'un antigèn
