Antibody-drug conjugates and immunotoxins
Inventors
Kontermann, Roland • Pfizenmaier, Klaus • Ferrer, Cristina • Fabre, Myriam • Simon, Laureano
Assignees
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Publication Number
US-10004812-B2
Publication Date
2018-06-26
Expiration Date
Abstract
The present invention relates to conjugates, in particular antibody-drug conjugates and immunotoxins, having the formula I: A-(L-D)p (I) or a pharmaceutically acceptable salts or solvates thereof, wherein: A is an antibody that selectively binds Endoglin; L is a linker; D is a drug comprising a cytolysin or a Nigrin-b A-chain; and p is 1 to 10, and to use of such conjugates in the therapeutic treatment of tumors. Methods of producing such conjugates and components for use in such methods are disclosed.
Core Innovation
The invention relates to a conjugate having the formula I, wherein A is an antibody that selectively binds Endoglin, L is a linker, D is a drug comprising a cytolysin, and p is 1 to 10. The conjugate is defined to be a pharmaceutically acceptable salt or solvate of the formula I conjugate.
The conjugate construction is further defined by the cytolysin formula IV constraints, including variables such as R2, R6, R7, R9, R10, f, q, R11, R16, and R17. This links the Endoglin-selective antibody component to a cytolysin drug component through linker L, with D containing the cytolysin of the defined structural family.
The description also provides example Endoglin-selective antibodies, including anti-human ENG and anti-murine ENG antibodies, and describes their use as A in ADC/immunotoxin formats using the conjugate formula A-(L-D)p. The document also states therapeutic use for tumors, including blood neoplasms and solid tumors, and for inflammatory and eye diseases.
Claims Coverage
The independent claim centers on one conjugate feature, supported by dependent claims that refine the antibody portion, refine linker architecture, refine drug and intermediate structures for the cytolysin-linker moiety, and introduce therapeutic use provisions together with co-administered agents.
Endoglin-selective antibody conjugated to cytolysin via linker L (p=1 to 10)
A conjugate having the formula I A-(L-D)p (or pharmaceutically acceptable salt or solvate), wherein A selectively binds Endoglin, L is a linker, D is a drug comprising a cytolysin, and p is 1 to 10.
Cytolysin of formula IV
The cytolysin in the conjugate is of formula IV, with defined structural constraints including R2, R6, R7, R9, R10, f, R11 with its structure, R16, R17 attached to linker L, and q=0, 1, 2 or 3.
CDR-defined Endoglin-binding antibody with SEQ ID NOs
In the antibody component A, the complementarity determining regions CDRH1-3 and CDRL1-3 are defined with specific amino-acid sequence identifiers (SEQ ID NOs 7 to 12).
Protease-cleavable linker architecture specified by maleimidocaproyl-valine-citrulline-p-aminobenzylcarbamate
In the conjugate, the linker L comprises maleimidocaproyl-valine-citrulline-p-aminobenzylcarbamate.
Spacer chain-length constraints (2 to 30 atoms)
The conjugate includes a spacer having a chain length of 2 to 30 atoms.
Spacer repeating-unit definition with n=1 to 10
The conjugate includes a spacer defined as —(CH2)n— or —(OCH2CH2)n— with n ranging from 1 to 10.
Co-administration with specified antitumor drugs
The method is defined such that one or more other antitumor drugs include one or more specified drugs and/or an anti-PD-1 or anti-PD-L1 molecule.
Overall, the claim set centers on an Endoglin-selective antibody conjugate in which linker L connects the antibody A to a cytolysin D, with p limited to 1 to 10. The cytolysin is constrained to formula IV, and dependent claims refine the antibody using specified CDR/SEQ ID NO definitions, refine the linker by specifying a named maleimidocaproyl-valine-citrulline-p-aminobenzylcarbamate linker and spacer chain-length/spacer repeating-unit ranges, and further define therapeutic method provisions including co-administration with specified antitumor drugs and anti-PD-1/anti-PD-L1 molecules.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Tumors, including blood neoplasms and solid tumors.
Inflammatory and eye diseases.
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