JPWO2021188590A5 - - Google Patents

Claims (34)

a first antigen-binding moiety that binds to CD117 expressed on hematopoietic stem cells (HSCs) or hematopoietic progenitor cells; and a second antigen-binding moiety that binds to an antigen expressed on T cells. Binding polypeptide. 2. The bispecific binding polypeptide of claim 1 , wherein the first antigen binding portion comprises an anti-CD117 single chain variable fragment (scFv) and the second antigen binding portion comprises an anti-CD3 scFv. The anti-CD117 binding portion is
(i) A heavy chain variable region comprising CDR1, CDR2, and CDR3 having the amino acid sequences set forth in SEQ ID NOs: 7, 8, and 9, respectively, and the amino acid sequences set forth in SEQ ID NOs: 10, 11, and 12, respectively. or (ii) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 14; or (iii) a heavy chain variable region comprising CDR1, CDR2, and CDR3 having the amino acid sequences set forth in SEQ ID NOs: 21, 22, and 23, respectively, and the amino acid sequences set forth in SEQ ID NOs: 24, 25, and 26, respectively. or (iv) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 27 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 28. 2. The bispecific binding polypeptide of claim 1 , comprising: The anti-CD3 binding portion is
(i) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 37 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 38; or (ii) comprising the amino acid sequence set forth in SEQ ID NO: 41. 4. The bispecific binding polypeptide of claim 3 , comprising a heavy chain variable region and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:45. A bispecific antibody or bispecific antigen-binding portion thereof comprising a CD117 binding region and a CD3 binding region, the CD117 binding region comprising:
(i) A heavy chain variable region comprising CDR1, CDR2, and CDR3 having the amino acid sequences set forth in SEQ ID NOs: 7, 8, and 9, respectively, and the amino acid sequences set forth in SEQ ID NOs: 10, 11, and 12, respectively. or (ii) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 14; or (iii) a heavy chain variable region comprising CDR1, CDR2, and CDR3 having the amino acid sequences set forth in SEQ ID NOs: 21, 22, and 23, respectively, and the amino acid sequences set forth in SEQ ID NOs: 24, 25, and 26, respectively. or (iv) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 27 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 28. said bispecific antibody or bispecific antigen-binding portion thereof. The CD3 binding region is
(i) the amino acid sequence set forth in SEQ ID NO: 37 and the amino acid sequence set forth in SEQ ID NO: 38; or (ii) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 41 and SEQ ID NO: 45 6. The bispecific antibody or bispecific antigen-binding portion thereof of claim 5 , comprising a light chain variable region comprising the amino acid sequence set forth in . 6. The bispecific antibody of claim 5 , wherein the Fc region comprises amino acid substitution(s) at position L234, L235, H435, or a combination thereof (EU index) compared to the wild-type Fc region. or a bispecific antigen binding portion thereof. 3. The Fc region comprises a first CH3 region comprising amino acid substitutions at positions T366, L368, and Y407 (EU index) and a second CH3 region comprising amino acid substitutions at position T366 (EU index). Item 5. The bispecific antibody or bispecific antigen-binding portion thereof according to item 5 . 9. The bispecific antibody or bispecific antigen binding portion thereof of claim 8 , wherein the amino acid substitution at position T366 is T366S , T366W or T366Y . 9. The bispecific antibody or bispecific antigen binding portion thereof of claim 8 , wherein the amino acid substitution at position L368 is L368A. 9. The bispecific antibody or bispecific antigen binding portion thereof of claim 8 , wherein the amino acid substitution at position Y407 is Y407V or Y407T. A pharmaceutical composition comprising a therapeutically effective amount of a bispecific binding polypeptide, bispecific antibody, or bispecific antigen binding portion thereof according to claim 1 . A method of treating a stem cell disorder in a human patient, comprising: a therapeutically effective amount of a bispecific binding polypeptide, a bispecific antibody, or a bispecific antigen binding thereof according to claim 1 ; said method comprising administering said portion. A method of treating an immunodeficiency disorder in a human patient, comprising: a therapeutically effective amount of a bispecific binding polypeptide, a bispecific antibody, or a bispecific antigen thereof according to claim 1; Said method comprising administering a binding moiety. 15. The method of claim 14 , wherein the immunodeficiency disorder is a congenital or acquired immunodeficiency. A method of treating a metabolic disorder in a human patient, comprising: a therapeutically effective amount of a bispecific binding polypeptide, a bispecific antibody, or a bispecific antigen binding thereof according to claim 1 ; said method comprising administering said portion. 17. The method of claim 16 , wherein the metabolic disorder is selected from the group consisting of glycogen storage diseases, mucopolysaccharidoses, Gaucher's disease, Hurler's disease, sphingolipidosis, and metachromatic leukodystrophy. A method of treating an autoimmune disorder in a human patient, comprising: a therapeutically effective amount of a bispecific binding polypeptide, a bispecific antibody, or a bispecific antigen thereof according to claim 1 ; Said method comprising administering a binding moiety. The autoimmune disorder may include multiple sclerosis, human systemic lupus, rheumatoid arthritis, inflammatory bowel disease, psoriasis treatment, type 1 diabetes mellitus, acute disseminated encephalomyelitis, Addison's disease, generalized alopecia, and ankylosing spine. inflammation, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune oophoritis, Barrow's disease, Behcet's disease, Bullous pemphigoid, cardiomyopathy, Chagas disease, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, Crohn's disease, cicatricial pemphigoid, celiac sprue-dermatitis herpetiformis, cold agglutinin disease , CREST syndrome, Degos disease, discoid lupus, autonomic neuropathy, endometriosis, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Goodpasture syndrome, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroid hidradenitis suppurativa, idiopathic and/or acute thrombocytopenic purpura, idiopathic pulmonary fibrosis, IgA neuropathy, interstitial cystitis, juvenile rheumatoid arthritis, Kawasaki disease, lichen planus, Lyme disease, Meniere's disease, mixed connective tissue disease, myasthenia gravis, myotonia nervosa, opsoclonus myoclonus syndrome, optic neuritis, ordothyroiditis, pemphigus vulgaris, pernicious anemia, polychondritis, polymyositis and dermatomyositis. , primary biliary cirrhosis, polyarteritis nodosa, polyglandular syndrome, polymyalgia rheumatica, primary agammaglobulinemia, Raynaud's phenomenon, Reiter syndrome, rheumatic fever, sarcoidosis, scleroderma, Sjögren's syndrome , systemic stiffness syndrome, Takayasu's arteritis, temporal arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo, vulvodynia, and Wegener's granulomatosis . Method. A method of treating cancer in a human patient, comprising: a therapeutically effective amount of a bispecific binding polypeptide, a bispecific antibody, or a bispecific antigen binding thereof according to claim 1 ; said method comprising administering said portion. 21. The method of claim 20 , wherein the cancer is selected from the group consisting of leukemia, lymphoma, multiple myeloma, and neuroblastoma. A method of depleting a population of stem cells in a human patient, comprising administering to the patient an effective amount of the bispecific binding polypeptide, bispecific antibody, or bispecific antigen binding portion thereof of claim 1. The method comprising administering. 23. The method of claim 22 , further comprising performing a transplant comprising hematopoietic stem cells in the patient. A method for selectively depleting hematopoietic stem cells (HSCs) in a human patient in need thereof, the method comprising: administering a bispecific antibody or bispecific antigen-binding portion thereof to the depletion of HSCs; , administering to said human subject in need thereof, said bispecific antibody or bispecific antigen binding portion thereof comprising a first binding portion that specifically binds to a human HSC cell surface antigen; said bispecific antibody or bispecific antigen-binding fragment thereof comprises a second binding moiety that specifically binds to a human T cell surface antigen; the Fc region comprising a second CH3 region of two heavy chains, wherein the first and second CH3 regions are capable of stably associating via a knob-in-hole interaction. The first antigen-binding portion is CD7, CDw12, CD13, CD15, CD19, CD21, CD22, CD29, CD30, CD33, CD34, CD36, CD38, CD40, CD41, CD42a, CD42b, CD42c, CD42d, CD43, CD48 , CD49b, CD49d, CD49e, CD49f, CD50, CD53, CD55, CD64a, CD68, CD71, CD72, CD73, CD81, CD82, CD85A, CD85K, CD90, CD99, CD104, CD105, CD109, CD110, C D111, CD112, CD114 , CD115, CD117, CD123, CD124, CD126, CD127, CD130, CD131, CD133, CD135, CD138, CD151, CD157, CD162, CD164, CD168, CD172a, CD173, CD174, CD175, C D175s, CD176, CD183, CD191, CD200 , CD201, CD205, CD217, CD220, CD221, CD222, CD223, CD224, CD225, CD226, CD227, CD228, CD229, CD230, CD235a, CD235b, CD236, CD236R, CD238, CD240 , CD242, CD243, CD277, CD292, CDw293 25. The method of claim 24 , wherein the method binds to a human HSC cell surface antigen selected from the group consisting of , CD295, CD298, CD309, CD318, CD324, CD325, CD338, CD344, CD349 and CD350. the first antigen-binding portion binds to CD117, the first antigen-binding portion
(i) A heavy chain variable region comprising CDR1, CDR2, and CDR3 having the amino acid sequences set forth in SEQ ID NOs: 7, 8, and 9, respectively, and the amino acid sequences set forth in SEQ ID NOs: 10, 11, and 12, respectively. or (ii) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 14; or (iii) a heavy chain variable region comprising CDR1, CDR2, and CDR3 having the amino acid sequences set forth in SEQ ID NOs: 21, 22, and 23, respectively, and the amino acid sequences set forth in SEQ ID NOs: 24, 25, and 26, respectively. or (iv) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 27 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 28. 25. The method of claim 24 , comprising: the second antigen binding portion binds to CD3; the second antigen binding portion binds to CD3;
(i) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 37 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 38; or (ii) comprising the amino acid sequence set forth in SEQ ID NO: 41. 27. The method of claim 26 , comprising a heavy chain variable region and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:45. 25. The first CH3 region comprises amino acid substitutions at positions T366, L368, and Y407 (EU index), and the second CH3 region comprises an amino acid substitution at position T366 (EU index). the method of. 29. The method of claim 28 , wherein the amino acid substitution at position T366 is T366S , T366W or T366Y . 29. The method of claim 28 , wherein the amino acid substitution at position L368 is L368A. 29. The method of claim 28 , wherein the amino acid substitution at position Y407 is Y407V or Y407T. 25. The method of claim 24 , wherein the patient has a stem cell disorder and is in need of a transplant. 33. The method of claim 32 , further comprising performing HSC transplantation on the patient after depletion. 25. The method of claim 24 , wherein the patient has an immunodeficiency disorder, metabolic disorder, autoimmune disorder, or cancer.