Humanized anti-CD73 antibodies
Inventors
Griffin, Emily Piccione • Miller, Richard A. • Frey, Gerhard Johann • Chang, Hwai Wen
Assignees
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Publication Number
US-11859007-B2
Publication Date
2024-01-02
Expiration Date
Abstract
Provided herein are, inter alia, humanized 1E9 antibodies capable of binding CD73. The humanized antibodies are useful for the treatment of cancer. Further provided are nucleic acids encoding humanized 1E9 antibodies and methods of inhibiting cell proliferation using the humanized antibodies provided herein.
Core Innovation
The invention relates to humanized 1E9 anti-CD73 antibodies. The antibodies comprise a humanized light chain variable region and a humanized heavy chain variable region, with explicit mouse CDR L1, L2, L3 and CDR H1, H2, H3 definitions and defined amino-acid substitutions at positions corresponding to Kabat positions using Kabat position substitutions and CDRs provided by SEQ ID NOs.
The humanized light chain variable region comprises mouse CDR L1 as set forth in SEQ ID NO:1, mouse CDR L2 as set forth in SEQ ID NO:2, and mouse CDR L3 as set forth in SEQ ID NO:3, together with specified amino-acid choices at Kabat positions corresponding to Kabat position 12, 43, 60, 74, 76, 77, 78, 80, 100, and 104. The humanized heavy chain variable region comprises mouse CDR H1 as set forth in SEQ ID NO:4, mouse CDR H2 as set forth in SEQ ID NO:5, and mouse CDR H3 as set forth in SEQ ID NO:6, together with specified amino-acid choices at Kabat positions corresponding to Kabat position 5, 7, 11, 12, 20, 38, 40, 66, 67, 69, 71, 73, 75, 83, and 87.
The invention further provides pH-dependent binding and potency across acidic to near-neutral conditions, including binding and potency at pH values less than about 7.5 and pH ranges centered around about 6.0-7.0. The antibodies are described as binding the CD73 antigen on cells, including lymphoid cells and T cells and cancer cells, and can inhibit CD73 catalytic activity.
Claims Coverage
The independent claims cover 2 inventive features.
Humanized 1E9 antibody with defined humanized light- and heavy-chain variable regions
A humanized 1E9 antibody comprising a humanized light chain variable region and a humanized heavy chain variable region, wherein the humanized light chain variable region comprises mouse CDR L1, CDR L2 and CDR L3 set forth in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3, and particular amino-acid residues at positions corresponding to Kabat positions 12, 43, 60, 74, 76, 77, 78, 80, 100 and 104; and wherein the humanized heavy chain variable region comprises mouse CDR H1, CDR H2 and CDR H3 set forth in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, and particular amino-acid residues at positions corresponding to Kabat positions 5, 7, 11, 12, 20, 38, 40, 66, 67, 69, 71, 73, 75, 83, and 87.
Humanized 1E9 antibody bound to CD73 at pH less than about 7.5 with specified Kabat-position residues
A humanized 1E9 antibody bound to a CD73 antigen at a pH of less than about 7.5, wherein the humanized light chain variable region comprises specified amino-acid residues at positions corresponding to Kabat positions 2, 4, 9, 10, 11, 14, 16, 18, 20 and 42, and wherein the humanized heavy chain variable region comprises specified amino-acid residues at positions corresponding to Kabat positions 1, 17, 20, 24, 37, 40, 41, 43, 44, 70, 75, 80, 83, 84, 85 and 89.
The independent claims cover a humanized 1E9 antibody defined by specified humanized light- and heavy-chain variable regions with mouse CDRs and defined Kabat-position substitutions, and a humanized 1E9 antibody bound to CD73 at a pH less than about 7.5 with specified Kabat-position substitutions in the humanized light- and heavy-chain variable regions.
Stated Advantages
pH-dependent binding/potency across acidic to near-neutral conditions, including pH <7.5 and pH ranges centered around about 6.0-7.0.
Inhibition of CD73 catalytic activity.
Blocks adenosine-mediated immune suppression.
Inhibits cell proliferation.
Enables cancer treatment.
Documented Applications
CD73-targeted therapeutic use in a cancer treatment context, including binding to CD73 on cancer cells and lymphoid cells and T cells.
CD73-dependent modulation of the AMP→adenosine pathway to reverse T-cell proliferation suppression.
Use of humanized 1E9 antibodies in pharmaceutical compositions and compositions including nucleic acids encoding the antibodies.
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