JP-2022530100-A5 -

Dates

Publication Date

20230501

Application Date

20200424

Description

The present invention will be better understood by referring to the following embodiments, but those skilled in the art will readily understand that the specific embodiments described in detail are merely illustrative examples of the invention, which are more fully described in the subsequent claims. Another aspect of the present invention may be as follows: [1] A method for targeted depletion of hematopoietic stem cells, wherein the method is This involves administering an effective amount of radiolabeled antibodies against CD34, CD117, CD135, or a combination thereof to the subject. A method wherein the radiolabeled antibody comprises a radiolabeling selected from 131 I, 125 I, 123 I, 90 Y, 177 Lu , 186 Re, 188 Re, 89 Sr, 153 Sm, 32 P , 225 Ac, 213 Bi, 213 Po , 211 At , 212 Bi, 213 Bi, 223 Ra, 227 Th, 149 Tb, 137 Cs, 212 Pb, and 103 Pd. [2] The method according to [2], wherein the radiolabeled antibody contains a 131I -radiolabeling, and the effective amount of the 131I -radiolabeling is 10 mCi to 200 mCi, or 200 mCi to 400 mCi, or 400 mCi to 1,200 mCi. [3] The method according to [2], wherein the radiolabeled antibody contains a 225Ac radiolabel, and the effective amount of the 225Ac radiolabel is 0.1 μCi/kg to 5.0 μCi/kg (target body weight), or 0.1 μCi/kg to 1.0 μCi/kg (target body weight), or 1.0 μCi/kg to 3.0 μCi/kg (target body weight), or 3.0 μCi/kg to 5.0 μCi/kg (target body weight). [4] The method according to [1], wherein the subject suffers from a non-cancerous disorder treatable via gene-edited cell therapy and is receiving such therapy to treat the non-cancerous disorder, and an effective amount of the radiolabeled antibody is administered as a single dose. [5] The method according to [4], wherein the non-cancerous disorder is selected from the group consisting of hemoglobin disorders, congenital immunodeficiency disorders, and viral infections. [6] The method according to [4], wherein the non-cancerous disorder is selected from the group consisting of sickle cell disease (SCD), severe combined immunodeficiency (SCID), and β-thalassemia. [7] The method according to [6], wherein the non-cancerous disorder is SCD and the therapy is genetically edited β-globin hematopoietic stem cell therapy. [8] The method according to [6], wherein the disorder is SCID, the therapy is gene-edited hematopoietic stem cell therapy, and the edited gene is selected from the group consisting of the common gamma chain (γc) gene, the adenosine deaminase (ADA) gene, and the Janus kinase 3 (JAK3) gene. [9] The method according to [1], wherein at least 50%, or at least 70%, or at least 90% of the hematopoietic stem cells are depleted, and less than 20%, or less than 10%, of the mature and differentiated hematopoietic stem cells are depleted. [10] The method according to [1], wherein the subject is suffering from a cancerous disorder treatable by bone marrow transplantation. [11] The method according to [10], wherein the cancerous disorder is leukemia or lymphoma. [12] The method according to [10], wherein the acute cancerous disorder is lymphoblastic leukemia, multiple myeloma, myelodysplastic syndrome, non-Hodgkin lymphoma, Hodgkin lymphoma, chronic lymphocytic leukemia, or a combination thereof. [13] A method for treating a subject suffering from a cancerous disorder treatable by bone marrow transplantation, wherein the method is (i) Administering to the subject a certain amount of radiolabeled antibody that is effective in depleting or destroying the hematopoietic stem cells of the subject, (ii) After an appropriate period of time, perform the bone marrow transplant on the subject in order to treat the subject's disorder, The cancerous disorder is leukemia or lymphoma, and the antibody comprises anti-CD34, anti-CD117, anti-CD135, or a combination thereof. A method wherein the radiolabeled antibody is labeled with 131 I, 125 I, 123 I, 90 Y, 177 Lu , 186 Re, 188 Re, 89 Sr, 153 Sm, 32 P, 225 Ac, 213 Bi, 213 Po, 211 At , 212 Bi, 213 Bi, 223 Ra, 227 Th, 149 Tb , 137 Cs, 212 Pb, or 103 Pd. [14] The method according to [13], wherein the acute cancerous disorder is lymphoblastic leukemia, multiple myeloma, myelodysplastic syndrome, non-Hodgkin lymphoma, Hodgkin lymphoma, chronic lymphocytic leukemia, or a combination thereof. [15] The method according to [13], wherein the hematopoietic stem cells are depleted by at least 70%, or at least 90%, and the mature and differentiated hematopoietic stem cells are depleted by less than 20%, or less than 10%. [16] The method according to [13], wherein the radiolabeled antibody contains a 131I-label, and the effective amount of the 131I -label is 10 mCi to 200 mCi administered 6, 7, or 8 days before the bone marrow transplant, or the effective amount of the 131I -label is 200 mCi to 400 mCi administered 8, 9, 10, 11, or 12 days before the bone marrow transplant, or the effective amount of the 131I -label is 400 mCi to 1,200 mCi administered 10, 11, 12, 13, or 14 days before the bone marro