Pyrrolobenzodiazepine antibody conjugates
Inventors
Thomas, Joshua D. • Jones, Brian D. • Lowinger, Timothy B. • Tang, Shuyi • YIN, Mao • Yurkovetskiy, Aleksandr V.
Assignees
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Publication Number
US-11638760-B2
Publication Date
2023-05-02
Expiration Date
Abstract
The present disclosure relates generally to antibody-drug conjugates comprising pyrrolo[2, 1-c][1, 4]benzodiazepine (PBD) drug moieties. The present disclosure also relates to methods of using these conjugates, e.g., as therapeutics and/or diagnostics.
Core Innovation
The invention relates to a conjugate of Formula (II) in which PBRM denotes a protein based recognition-molecule and each occurrence of D is independently a PBD drug moiety of Formula (IV), including tautomer, pharmaceutically acceptable salt or solvate forms. The PBD drug moiety is directly or indirectly linked to the PBRM via functional groups of E, E′, D′, R7, and R10, with defined linkage to the PBRM through corresponding functional-group connectors.
The structural definition further specifies T as a C1-10 alkylene linker and A as a peptide moiety containing at least two amino acids, with the NH group of A connected to the C(O)-T moiety of Formula (IV) and the C(O) moiety of A connected to E. The disclosure also includes T′ as a hydrophilic group directly or indirectly attached to M_A, L_P′ as a divalent linker moiety connecting the PBRM to M_P, and broad substituent and variable definitions within the Formula (II) framework.
A central feature of the conjugate is a divalent linker moiety L_D connecting D to M_A and comprising at least one cleavable bond such that, when the bond is broken, D is released in an active form for its intended therapeutic effect. The disclosure also describes D′ as D1, D2, D3, or D4, dotted-line indications in D1 or D4 showing the presence of a single or double bond, and m defined as 0, 1, or 2.
The disclosure further includes formula-based selection of conjugates from Formulae (XIVi), (XIVj), and (XIVo), including tautomer, pharmaceutically acceptable salt, and solvate forms. The conjugate architecture combines the PBRM-linked drug moiety, defined functional-group connection points, the linker and peptide-containing attachment region, and the cleavable-release feature.
Claims Coverage
Two independent claim themes are present: a broad Formula (II) PBRM-PBD drug moiety conjugate with defined linkage and cleavable-release architecture, and a formula-selection claim covering conjugates selected from Formulae (XIVi), (XIVj), and (XIVo). In total, the consolidated claim coverage reflects four principal inventive features.
Protein based recognition-molecule conjugate with PBD drug moieties
A conjugate of Formula (II) wherein PBRM denotes a protein based recognition-molecule and each occurrence of D is independently a PBD drug moiety of Formula (IV), including tautomer, pharmaceutically acceptable salt or solvate forms.
Defined linkage architecture via E, E′, D′, R7, and R10
The PBD drug moiety is directly or indirectly linked to the PBRM via functional groups of E, E′, D′, R7, and R10, with direct or indirect linkage to the PBRM defined through the corresponding functional-group connectors.
C1-10 alkylene linker and peptide-containing A region
T is a C1-10 alkylene linker and A comprises a peptide moiety containing at least two amino acids, with the NH group of A connected to the C(O)-T moiety of Formula (IV) and the C(O) moiety of A connected to E; T′ is a hydrophilic group directly or indirectly attached to M_A, and L_P′ connects the PBRM to M_P.
Cleavable linker L_D releasing D in an active form
L_D is a divalent linker moiety connecting D to M_A and comprises at least one cleavable bond such that when the bond is broken, D is released in an active form for its intended therapeutic effect; D′ is D1, D2, D3, or D4, with dotted-line indications in D1 or D4 denoting a single or double bond and m defined as 0, 1, or 2.
The consolidated claim coverage centers on a PBRM-PBD conjugate of Formula (II) with defined functional-group linkage points, a C1-10 alkylene linker and peptide-containing attachment region, and a cleavable linker that releases D in active form. A further independent claim covers selected conjugates from Formulae (XIVi), (XIVj), and (XIVo), including tautomer and pharmaceutically acceptable salt or solvate forms.
Stated Advantages
Releases D in an active form for its intended therapeutic effect when the cleavable bond is broken.
Bystander killing effects.
High membrane permeability of the PBD drug moiety versus low-permeability hydrolysis products.
Reduced efflux via P-gp efflux pumps.
T′ is described as substantially non-antigenic and water-soluble.
Lack of susceptibility to P-gp efflux in certain embodiments.
Documented Applications
Treating cancer by administering to a subject in need thereof a pharmaceutically effective amount of the conjugate.
Pharmaceutical composition use cases comprising the conjugates in pharmaceutically acceptable carriers.
Combination therapy with immune checkpoint inhibitors including CTLA-4, PD-1, PD-L1, PD-L2, LAG3, TIM3, B7-H3, CD137, and IDO1, together with PARP inhibitor and other cytotoxic agents.
Diagnostic/prophylactic use categories including diagnostic labels, PET, MRI contrast agent, and gamma scintigraphy.
Biological evaluation in vitro using CellTiter-Glo cell viability/IC50 across HER2-expressing and low-expressing cell lines for illustrative trastuzumab-PBD conjugates.
In vivo tumor growth response in CB-17 SCID mice bearing Calu-3 xenografts for multiple trastuzumab-PBD conjugates.
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