US 12,251,448 B2
Compositions and methods for the depletion of CD5+ cells
Anthony Boitano, Newton, MA (US); Michael Cooke, Boston, MA (US); Rahul Palchaudhuri, Somerville, MA (US); and Sean McDonough, Littleton, MA (US)
Assigned to Heidelberg Pharma Research GmbH, Ladenburg (DE)
Filed by Heidelberg Pharma Research Gmbh, Ladenburg (DE)
Filed on Apr. 29, 2021, as Appl. No. 17/244,721.
Application 17/244,721 is a continuation of application No. 16/851,082, filed on Apr. 16, 2020, abandoned.
Application 16/851,082 is a continuation of application No. PCT/US2018/063175, filed on Nov. 29, 2018.
Claims priority of provisional application 62/592,214, filed on Nov. 29, 2017.
Prior Publication US 2021/0369854 A1, Dec. 2, 2021
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 47/68 (2017.01); A61K 38/12 (2006.01); A61K 39/00 (2006.01); C07K 16/28 (2006.01)
CPC A61K 47/6803 (2017.08) [A61K 38/12 (2013.01); A61K 47/6849 (2017.08); C07K 16/2896 (2013.01); A61K 2039/505 (2013.01); C07K 2317/92 (2013.01)] 13 Claims
 
1. A method of depleting a population of CD5+ cells in a human patient, the method comprising:
administering to the human patient an effective amount of an anti-CD5 antibody 5D7 or antigen-binding fragment thereof,
wherein the antibody, or antigen-binding fragment thereof, is conjugated to a cytotoxin, to form an anti-CD5 antibody 5D7 antibody drug conjugate,
wherein the cytotoxin is an amatoxin,
wherein the anti-CD5 antibody 5D7 antibody drug conjugate has a drug to antibody ratio of about 6 or 2, wherein the conjugation is site-specific via a D265C mutation, and
wherein the antibody or antigen-binding fragment thereof conjugated to a cytotoxin is represented by the formula Ab-Z-L-Am, wherein Ab is the antibody or antigen-binding fragment thereof, L is a linker, Z is a chemical moiety, and Am is an amatoxin represented by formula (I)

OG Complex Work Unit Chemistry
wherein R1 is H, OH, ORA, or ORC;
R2 is H, OH, ORB, or ORC;
RA and RB, when present, together with the oxygen atoms to which they are bound, combine to form an 5-membered heterocycloalkyl group;
R3 is H, RC, or RD;
R4, R5, R6, and R7 are each independently H, OH, ORC, ORD, RC, or RD;
R8 is OH, NH2, ORC, ORD, NHRC, or NRCRD;
R9 is H, OH, ORC, or ORD;
X is —S—, —S(O)—, or —SO2—;
RC is -L-Z;
RD is C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 heteroalkenyl, C2-C6 alkynyl, C2-C6 heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
L is C1-C6 alkylene, C1-C6 heteroalkylene, C2-C6 alkenylene, C2-C6 heteroalkenylene, C2-C6 alkynylene, C2-C6 heteroalkynylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene; a dipeptide, —C(═O)—, a peptide, or a combination thereof; and
Z is a chemical moiety formed from a coupling reaction between a reactive substituent present on L and a reactive substituent present within the antibody or antigen-binding fragment thereof,
wherein Am comprises exactly one RC substituent, and wherein said antibody or antigen-binding fragment thereof comprises the following complementarity determining regions (CDRs):
a. a CDR-H1 having the amino acid sequence GYTFTNY (SEQ ID NO: 3);
b. a CDR-H2 having the amino acid sequence NTHTGE (SEQ ID NO: 4);
c. a CDR-H3 having the amino acid sequence RGYDWYFDV (SEQ ID NO: 5);
d. a CDR-L1 having the amino acid sequence RASQDINSYLS (SEQ ID NO: 6);
e. a CDR-L2 having the amino acid sequence RANRLVD (SEQ ID NO: 7); and
f. a CDR-L3 having the amino acid sequence QQYDESPWT (SEQ ID NO: 8); or
a. a CDR-H1 having the amino acid sequence FSLSTSGMG (SEQ ID NO: 29);
b. a CDR-H2 having the amino acid sequence WWDDD (SEQ ID NO: 30);
c. a CDR-H3 having the amino acid sequence RRATGTGFDY (SEQ ID NO: 31);
d. a CDR-L1 having the amino acid sequence QDVGTA (SEQ ID NO: 32);
e. a CDR-L2 having the amino acid sequence WTSTRHT (SEQ ID NO: 33);
f. a CDR-L3 having the amino acid sequence YNSYNT (SEQ ID NO: 34).