US 10,376,583 B2
Human immunodeficiency virus therapies utilizing N332-glycan-dependent antibodies and a reservoir activator
Dan H. Barouch, Newton, MA (US)
Assigned to Beth Israel Deaconess Medical Center, Inc., Boston, MA (US)
Appl. No. 15/25,961
Filed by Beth Israel Deaconess Medical Center, Inc., Boston, MA (US)
PCT Filed Sep. 30, 2014, PCT No. PCT/US2014/058383
§ 371(c)(1), (2) Date Mar. 30, 2016,
PCT Pub. No. WO2015/048770, PCT Pub. Date Apr. 2, 2015.
Claims priority of provisional application 61/884,414, filed on Sep. 30, 2013.
Prior Publication US 2016/0213779 A1, Jul. 28, 2016
Int. Cl. A61K 39/42 (2006.01); C07K 16/10 (2006.01); A61K 39/395 (2006.01); A61K 45/06 (2006.01); A61K 39/00 (2006.01)
CPC A61K 39/42 (2013.01) [A61K 39/3955 (2013.01); A61K 45/06 (2013.01); C07K 16/1045 (2013.01); C07K 16/1063 (2013.01); A61K 2039/505 (2013.01); A61K 2039/507 (2013.01); C07K 2317/565 (2013.01); C07K 2317/76 (2013.01); C07K 2317/94 (2013.01)] 73 Claims
 
1. A method for inhibiting viral replication, reducing proviral DNA, or reducing viral load comprising administering to a subject infected with human immunodeficiency virus type 1 (HIV-1) a first regimen comprising one or more doses of an N332 glycan-dependent antibody and a reservoir activator until a proviral DNA level in a tissue of the subject is below about 1,000 DNA copies/106 cells, and, at least two months after completion of the first regimen, administering a second regimen comprising one or more doses of the N332 glycan-dependent antibody with or without a reservoir activator, wherein said N332 glycan-dependent antibody is selected from the group consisting of:
(a) an antibody comprising:
(i) a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6; or
(ii) a heavy chain variable domain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7, and a light chain variable domain having at least 97% sequence identity to the sequence of SEQ ID NO: 8;
(b) an antibody comprising
a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 9, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 10, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 11, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 12, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 13, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 14;
(c) an antibody comprising
a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22;
(d) an antibody comprising
a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 137, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 138, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 139, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 140, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 142, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 143;
(e) an antibody comprising
a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 25, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 26, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 27, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 28, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 29, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 30;
(f) an antibody comprising
a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 33, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 34, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 35, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 36, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 37, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 38;
(g) an antibody comprising
a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 41, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 42, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 43, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 44, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 46;
(h) an antibody comprising
a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 49, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 50, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 51, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 52, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 53, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 54;
(i) an antibody comprising
a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 57, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 58, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 59, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 60, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 61, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 62;
(j) an antibody comprising
a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 145, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 146, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 147, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 148, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 149, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 150;
(k) an antibody comprising
a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 153, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 154, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 155, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 156, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 157, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 158;
(l) an antibody comprising
a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 73, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 74, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 75, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 76, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 77, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 78;
(m) an antibody comprising
a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 81, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 82, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 83, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 84, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 85, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 86;
(n) an antibody comprising
a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 97, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 98, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 99, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 100, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 101, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 102;
(o) an antibody comprising
a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 169, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 170, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 171, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 172, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 173, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 174;
(p) an antibody comprising
a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 177, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 178, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 179, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 180, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 181, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 182; and
(q) an antibody comprising
a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 315, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 316, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 317, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 318, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 319, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 320.