1. An anti-ROR1 antibody capable of inducing cell death in a cell expressing ROR1.
2. An antibody as claimed in claim 1 wherein the antibody binds specifically to either an extracellular domain of ROR1, an intracellular domain of ROR 1 or to a nucleotide sequence encoding ROR 1.
3. An antibody as claimed in claim 1 wherein the antibody is either a complete antibody or a fragment thereof.
4. An antibody as claimed in any previous claim wherein cell death is induced on specific binding of the antibody to ROR1 or the nucleotide sequence encoding ROR1.
5. An antibody as claimed in claim 1 wherein the extracellular domain to which the antibody binds has the amino acid sequence of SEQ ID NO: 1).
6. An antibody as claimed in claim 1 wherein the intracellular domain to which the antibody binds has the amino acid sequence of SEQ ID NO: 2.
7. An antibody as claimed in claim 1 comprising the combination of VH and VL region amino acid sequences of:
SEQ ID NO: 5 and SEQ ID NO: 6,
SEQ ID NO: 7 and SEQ ID NO: 8,
SEQ ID NO: 9 and SEQ ID NO: 10,
SEQ ID NO: 11 and SEQ ID NO: 12,
SEQ ID NO: 13 and SEQ ID NO: 14,
SEQ ID NO: 15 and SEQ ID NO: 16,
SEQ ID NO: 17 and SEQ ID NO: 18,
SEQ ID NO: 19 and SEQ ID NO: 20,
SEQ ID NO: 21 and SEQ ID NO: 22,
SEQ ID NO: 23 and SEQ ID NO: 24,
SEQ ID NO: 25 and SEQ ID NO: 26,
SEQ ID NO: 27 and SEQ ID NO: 28, or
SEQ ID NO: 29 and SEQ ID NO: 30.
8. An antibody as claimed in claim 1 comprising a combination of all six CDR regions having the following amino acid sequences:
(a) CDRH1, SEQ ID NO: 57; CDRH2, SEQ ID NO: 58; CDRH3, SEQ ID NO: 59, CDRL1, SEQ ID NO: 60; CDRL2, SEQ ID NO: 61; and CDRL3, SEQ ID NO: 62;
(b) CDRH1, SEQ ID NO: 63; CDRH2, SEQ ID NO: 64; CDRH3, SEQ ID NO: 65, CDRL1, SEQ ID NO: 66; CDRL2, SEQ ID NO: 67; and CDRL3, SEQ ID NO: 68;
(c) CDRH1, SEQ ID NO: 69; CDRH2, SEQ ID NO: 70; CDRH3, SEQ ID NO: 71, CDRL1, SEQ ID NO: 72; CDRL2, SEQ ID NO: 73; and CDRL3, SEQ ID NO: 74;
(d) CDRH1, SEQ ID NO: 75; CDRH2, SEQ ID NO: 76; CDRH3, SEQ ID NO: 77, CDRL1, SEQ ID NO: 78; CDRL2, SEQ ID NO: 79; and CDRL3, SEQ ID NO: 80;
(e) CDRH1, SEQ ID NO: 81; CDRH2, SEQ ID NO: 82; CDRH3, SEQ ID NO: 83, CDRL1, SEQ ID NO: 84; CDRL2, SEQ ID NO: 85; and CDRL3, SEQ ID NO: 86;
(f) CDRH1, SEQ ID NO: 87; CDRH2, SEQ ID NO: 88; CDRH3, SEQ ID NO: 89, CDRL1, SEQ ID NO: 90; CDRL2, SEQ ID NO: 91; and CDRL3, SEQ ID NO: 92;
(g) CDRH1, SEQ ID NO: 93; CDRH2, SEQ ID NO: 94; CDRH3, SEQ ID NO: 95, CDRL1, SEQ ID NO: 96; CDRL2, SEQ ID NO: 97; and CDRL3, SEQ ID NO: 98;
(h) CDRH1, SEQ ID NO: 99; CDRH2, SEQ ID NO: 100; CDRH3, SEQ ID NO: 101, CDRL1, SEQ ID NO: 102; CDRL2, SEQ ID NO: 103; and CDRL3, SEQ ID NO: 104;
(i) CDRH1, SEQ ID NO: 105; CDRH2, SEQ ID NO: 106; CDRH3, SEQ ID NO: 107, CDRL1, SEQ ID NO: 108; CDRL2, SEQ ID NO: 109; and CDRL3, SEQ ID NO: 110;
(j) CDRH1, SEQ ID NO: 111; CDRH2, SEQ ID NO: 112; CDRH3, SEQ ID NO: 113, CDRL1, SEQ ID NO: 114; CDRL2, SEQ ID NO: 115; and CDRL3, SEQ ID NO: 116;
(k) CDRH1, SEQ ID NO: 117; CDRH2, SEQ ID NO: 118; CDRH3, SEQ ID NO: 119, CDRL1, SEQ ID NO: 120; CDRL2, SEQ ID NO: 121; and CDRL3, SEQ ID NO: 122;
(l) CDRH1, SEQ ID NO: 123; CDRH2, SEQ ID NO: 124; CDRH3, SEQ ID NO: 125, CDRL1, SEQ ID NO: 126; CDRL2, SEQ ID NO: 127; and CDRL3, SEQ ID NO: 128: or
(m) CDRH1, SEQ ID NO: 129; CDRH2, SEQ ID NO: 130; CDRH3, SEQ ID NO: 131, CDRL1, SEQ ID NO: 132; CDRL2, SEQ ID NO: 133; and CDRL3, SEQ ID NO: 134.
9. An antibody as claimed in claim 1 comprising at least one, of the following CDR regions:
(a) CDRH1, SEQ ID NO: 57; CDRH2, SEQ ID NO: 58; CDRH3, SEQ ID NO: 59, CDRL1, SEQ ID NO: 60; CDRL2, SEQ ID NO: 61; andor CDRL3, SEQ ID NO: 62;
(b) CDRH1, SEQ ID NO: 63; CDRH2, SEQ ID NO: 64; CDRH3, SEQ ID NO: 65, CDRL1, SEQ ID NO: 66; CDRL2, SEQ ID NO: 67; andor CDRL3, SEQ ID NO: 68;
(c) CDRH1, SEQ ID NO: 69; CDRH2, SEQ ID NO: 70; CDRH3, SEQ ID NO: 71, CDRL1, SEQ ID NO: 72; CDRL2, SEQ ID NO: 73; andor CDRL3, SEQ ID NO: 74;
(d) CDRH1, SEQ ID NO: 75; CDRH2, SEQ ID NO: 76; CDRH3, SEQ ID NO: 77, CDRL1, SEQ ID NO: 78; CDRL2, SEQ ID NO: 79; andor CDRL3, SEQ ID NO: 80;
(e) CDRH1, SEQ ID NO: 81; CDRH2, SEQ ID NO: 82; CDRH3, SEQ ID NO: 83, CDRL1, SEQ ID NO: 84; CDRL2, SEQ ID NO: 85; andor CDRL3, SEQ ID NO: 86;
(f) CDRH1, SEQ ID NO: 87; CDRH2, SEQ ID NO: 88; CDRH3, SEQ ID NO: 89, CDRL1, SEQ ID NO: 90; CDRL2, SEQ ID NO: 91; andor CDRL3, SEQ ID NO: 92;
(g) CDRH1, SEQ ID NO: 93; CDRH2, SEQ ID NO: 94; CDRH3, SEQ ID NO: 95, CDRL1, SEQ ID NO: 96; CDRL2, SEQ ID NO: 97; andor CDRL3, SEQ ID NO: 98;
(h) CDRH1, SEQ ID NO: 99; CDRH2, SEQ ID NO: 100; CDRH3, SEQ ID NO: 101, CDRL1, SEQ ID NO: 102; CDRL2, SEQ ID NO: 103; andor CDRL3, SEQ ID NO: 104;
(i) CDRH1, SEQ ID NO: 105; CDRH2, SEQ ID NO: 106; CDRH3, SEQ ID NO: 107, CDRL1, SEQ ID NO: 108; CDRL2, SEQ ID NO: 109; andor CDRL3, SEQ ID NO: 110;
(j) CDRH1, SEQ ID NO: 111; CDRH2, SEQ ID NO: 112; CDRH3, SEQ ID NO: 113, CDRL1, SEQ ID NO: 114; CDRL2, SEQ ID NO: 115; andor CDRL3, SEQ ID NO: 116;
(k) CDRH1, SEQ ID NO: 117; CDRH2, SEQ ID NO: 118; CDRH3, SEQ ID NO: 119, CDRL1, SEQ ID NO: 120; CDRL2, SEQ ID NO: 121; andor CDRL3, SEQ ID NO: 122;
(l) CDRH1, SEQ ID NO: 123; CDRH2, SEQ ID NO: 124; CDRH3, SEQ ID NO: 125, CDRL1, SEQ ID NO: 126; CDRL2, SEQ ID NO: 127; andor CDRL3, SEQ ID NO: 128: or
(m) CDRH1, SEQ ID NO: 129; CDRH2, SEQ ID NO: 130; CDRH3, SEQ ID NO: 131, CDRL1, SEQ ID NO: 132; CDRL2, SEQ ID NO: 133; andor CDRL3, SEQ ID NO: 134.
10. An antibody as claimed in any of claims 7 to 9 further comprising the constant region CH, having the amino acid sequence of SEQ ID NO: 3 and the constant region CL having the amino acid sequence of SEQ ID NO: 4.
11. (canceled)
12. An antibody that competitively binds to the same epitope as the antibodies of claim 1.
13. (canceled)
14. A nucleotide sequence encoding an antibody as claimed in claim 1.
15. A nucleotide sequence as claimed in claim 14 wherein the nucleotide sequences are:
(a) SEQ ID NO: 31 and SEQ ID NO: 32;
(b) SEQ ID NO: 33 and SEQ ID NO: 34;
(c) SEQ ID NO: 35 and SEQ ID NO: 36;
(d) SEQ ID NO: 37 and SEQ ID NO: 38;
(e) SEQ ID NO: 39 and SEQ ID NO: 40;
(f) SEQ ID NO: 41 and SEQ ID NO: 42;
(g) SEQ ID NO: 43 and SEQ ID NO: 44;
(h) SEQ ID NO: 45 and SEQ ID NO: 46;
(i) SEQ ID NO: 47 and SEQ ID NO: 48;
(j) SEQ ID NO: 49 and SEQ ID NO: 50;
(k) SEQ ID NO: 51 and SEQ ID NO: 52;
(l) SEQ ID NO: 53 and SEQ ID NO: 54; or
(m) SEQ ID NO: 55 and SEQ ID NO: 56.
16.-25. (canceled)
26. A pharmaceutical composition comprising an antibody as defined in claim 1 and a pharmaceutically acceptable excipient, diluent or carrier.
27. (canceled)
28. A kit of parts comprising:
(i) an antibody as claimed in claim 1 or a pharmaceutical composition as claimed in claim 26;
(ii) apparatus for administering the antibody or pharmaceutical composition; and
(iii) instructions for use.
29.-33. (canceled)
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A method of preparing a degradable nanoparticle comprising the step of reacting a polymer comprising at least one monomer residue having a structure represented by a formula:
wherein Z is O, S, or NR, wherein R is H, alkyl, or aryl; and
wherein m and n are independently non-negative integers;
with a dinucleophile having a structure X\u2014RL\u2014X\u2032, wherein X and X\u2032 are independently OH, SH, NH2, or NHR, wherein R is H, alkyl, or aryl, and wherein RL is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxylene, and optionally substituted esters,
thereby producing nanoparticles.
2. The method of claim 1, wherein reacting is adding a polymer comprising at least one monomer residue having a structure represented by a formula:
wherein Z is O or NR, wherein R is H or C1 to C6 alkyl, wherein m is an integer from 0 to 6, and wherein n is an integer from 0 to 2;
to a solution of from about 1 to about 10 molar equivalents of a dinucleophile (nucleophilic moiety:epoxide functionality) having a structure X\u2014RL\u2014X\u2032, wherein X and X\u2032 are independently OH, SH, NH2, or NHR, wherein R is H or C1 to C6 alkyl, and wherein RL is selected from optionally substituted alkyl and optionally substituted alkoxylene.
3. The method of claim 1, wherein reacting is contacting a polymer comprising at least one monomer residue having a structure represented by a formula:
wherein Z is O or NR, wherein R is H or C1 to C6 alkyl, wherein m is an integer from 0 to 6, and wherein n is an integer from 0 to 2;
with a solution of at least one molar equivalent of the dinucleophile.
4. The method of claim 3, wherein the solution comprises from about 1 molar equivalent of a dinucleophile and the resultant nanoparticle has a particle size of from about 5 nm to about 55 nm.
5. The method of claim 3, wherein the solution comprises from about 2 molar equivalents of a dinucleophile and the resultant nanoparticle has a particle size of from about 30 nm to about 80 nm.
6. The method of claim 3, wherein the solution comprises from about 3 molar equivalents of a dinucleophile and the resultant nanoparticle has a particle size of from about 70 nm to about 13 nm.
7. The method of claim 3, wherein the solution comprises from about 4 molar equivalents of a dinucleophile and the resultant nanoparticle has a particle size of from about 110 nm to about 170 nm.
8. The method of claim 3, wherein the solution comprises from about 5 molar equivalents of a dinucleophile and the resultant nanoparticle has a particle size of from about 175 nm to about 300 nm.
9. The method of claim 3, wherein the solution comprises from about 6 molar equivalents of a dinucleophile and the resultant nanoparticle has a particle size of from about 250 nm to about 350 nm.
10. The method of claim 3, wherein the solution comprises from about 8 molar equivalents of a dinucleophile and the resultant nanoparticle has a particle size of from about 400 nm to about 550 nm.
11. The method of claim 3, wherein the solution comprises from about 10 molar equivalents of a dinucleophile and the resultant nanoparticle has a particle size of from about 650 nm to about 850 nm.
12. The method of claim 1, wherein the monomer residue comprises less than about 10% by weight of the monomer residue of halogen selected from chlorine, bromine, and iodine.
13. The method of claim 1, wherein Z is O.
14. The method of claim 1, wherein the nanoparticle is further substituted with at least one biologically active agent, at least one pharmaceutically active agent, andor at least one imaging moiety.
15. The method of claim 1, further comprising the step of administering to a subject an effective amount of the degradable nanoparticle, wherein the nanoparticle is further substituted with at least one biologically active agent, at least one pharmaceutically active agent, andor at least one imaging moiety.
16. The method of claim 1, wherein the nanoparticle has at least one epoxide-functionalized monomer residue, the method further comprising the step of reacting the nanoparticle with a nucleophile having a structure represented by a formula X\u2014R1,
wherein X is OH, SH, NH2, or NHR, wherein R is H or C1 to C6 alkyl; and
wherein R1 is an optionally substituted organic radical comprising 1 to 24 carbon atoms, thereby functionalizing the nanoparticle.
17. The method of claim 16, wherein Z is O.
18. The method of claim 17, wherein X is NH2 or NHR.
19. The method of claim 17, R1 is further substituted with at least one biologically active agent, at least one pharmaceutically active agent, andor at least one imaging moiety.