25-08-2022 дата публикации
Номер: US20220267442A1
Принадлежит:
The present disclosure provides fusion proteins that specifically inhibit transforming growth factor-β (TGF-β) signaling in CD4+ helper T cells, and engineered CD4+ helper T cells that are deficient in TGF-β signaling, to counteract tumor-induced immune tolerance and promote anti-tumor immunity. The fusion proteins and engineered CD4+ helper T cells of the present technology are useful in methods for treating cancer, and enhancing the efficacy of other therapeutic agents against refractory cancer cells. 1. A fusion protein comprising a CD4 targeting moiety fused with an immunomodulatory moiety , wherein:{'sub': H', 'L, 'claim-text': [{'sub': H', 'H', 'H', 'H, '(a) the Vcomprises a V-CDR1 sequence of GYTFTSYVIH (SEQ ID NO: 6), a V-CDR2 sequence of YINPYNDGTDYDEKFKG (SEQ ID NO: 7), and a V-CDR3 sequence of EKDNYATGAWFAY (SEQ ID NO: 8), and'}, {'sub': L', 'L', 'L', 'L', 'H', 'L, '(b) the Vcomprises a V-CDR1 sequence of KSSQSLLYSTNQKNYLA (SEQ ID NO: 2), a V-CDR2 sequence of WASTRES (SEQ ID NO: 3), and a V-CDR3 sequence of QQYYSYRT (SEQ ID NO: 4), optionally wherein the Vcomprises an amino acid sequence that is at least 80%, at least 85%, at least 95%, or 100% identical to SEQ ID NO: 5; and/or the Vcomprises an amino acid sequence that is at least 80%, at least 85%, at least 95%, or 100% identical to SEQ ID NO: 1; and'}], 'the CD4 targeting moiety comprises a heavy chain immunoglobulin variable domain (V) and a light chain immunoglobulin variable domain (V), whereinthe immunomodulatory moiety comprises an amino acid sequence of TGF-β receptor II (TGF-βRII) selected from the group consisting of SEQ ID NOs: 11-12 and 15-17.2. The fusion protein of claim 1 , wherein the CD4 targeting moiety comprises an antibody or an antigen binding fragment that specifically binds a CD4 epitope optionally whereinthe antibody or antigen binding fragment further comprises a Fc domain of an isotype selected from the group consisting of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM, IgD, and IgE; ...
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