Anti-ROR1 antibody conjugates, compositions comprising anti ROR1 antibody conjugates, and methods of making and using anti-ROR1 antibody conjugates preliminary class
Inventors
Gakhal, Amandeep • YU, Abigail • Stafford, Ryan • Hanson, Jeffrey • Yam, Alice • Bajjuri, Krishna • Maderna, Andreas • Abrahams, Cristina • Li, Xiaofan • Yin, Gang • Wen, Miao • Bedard, Kristin • Calarese, Daniel • Kiefel, Helena
Assignees
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Publication Number
US-12226490-B2
Publication Date
2025-02-18
Expiration Date
Abstract
The present disclosure relates to antibodies and antibody conjugates, for instance antibody drug conjugates, with binding specificity for receptor tyrosine kinase orphan receptor 1 (ROR1) and its isoforms and homologs, and compositions comprising the antibodies or antibody conjugates, including pharmaceutical compositions. Also provided are methods of producing the antibodies and antibody conjugates and compositions thereof as well as methods of using the antibodies and antibody conjugates and compositions thereof, such as in therapeutic and diagnostic methods.
Core Innovation
The invention relates to an antibody conjugate comprising an antibody that specifically binds to receptor tyrosine kinase orphan receptor 1 (ROR1) and is linked site-specifically to at least one payload moiety. The antibody comprises one or more non-natural amino acids, and the conjugate is according to a structure of Formula I or a pharmaceutically acceptable salt thereof. The structure includes COMP as a residue of the anti-ROR1 antibody, together with a defined linker region and a payload-linked framework.
Within Formula I, L1 is C1-6 alkylene and Y is defined by alkylene, alkenylene, or alkynylene segments with substitution patterns selected from R50 and optionally R51. R50 is defined as an alkylene-X2-[alkylene]m-POLY, alkenylene-X2-[alkenylene]m-POLY, or alkynylene-X2-[alkynylene]m-POLY form, where POLY is a water-soluble polymer. X1 and X2 are independently selected from C(O) and N(R10)C(O), and the structure also defines Su as a hexose form of a monosaccharide, D as a drug moiety, and RL as a reactive group residue.
The disclosure also provides defined substitution classes for R50 and R51, including halogen, cyano, nitro, hydroxyl, N(R10)2, C(O)N(R10)2, C(O), C(S), C(O)OCH2C6H5, NHC(O)OCH2C6H5, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl. The structure further specifies integer parameters n, m, and p within the Formula I framework. Some items also describe exemplary linker-payload embodiments and ROR1-binding antibody variable-region sequence definitions, including specified CDR selections and SEQ ID ranges.
Claims Coverage
The consolidated claim coverage centers on a site-specific anti-ROR1 antibody conjugate with one or more non-natural amino acids and a Formula I-defined linker/payload architecture. The main inventive features combine the ROR1-binding antibody, the COMP residue, the L1 and Y linker system, polymer-bearing substituent groups R50 and optional R51, and the defined roles of POLY, Su, D, and RL.
Anti-ROR1 antibody conjugate with non-natural amino acids
An antibody conjugate comprising an antibody that specifically binds to receptor tyrosine kinase orphan receptor 1 (ROR1) linked site-specifically to at least one payload moiety, wherein the antibody comprises one or more non-natural amino acids.
Formula I conjugate architecture with COMP, L1, and Y
The antibody conjugate is according to the structure of Formula I or a pharmaceutically acceptable salt thereof, wherein COMP is a residue of the anti-ROR1 antibody comprising one or more non-natural amino acids; L1 is C1-6 alkylene; and Y comprises alkylene, alkenylene, or alkynylene segments.
Y substituted with R50 and optionally R51
At least one alkylene, alkenylene, or alkynylene in Y is substituted with one or more substituents selected from R50, and the alkylene, alkenylene, or alkynylene in Y is optionally substituted with one or more substituents selected from R51.
Water-soluble polymer-bearing R50 substituents
R50 is selected from alkylene-X2-[alkylene]m-POLY, alkenylene-X2-[alkenylene]m-POLY, or alkynylene-X2-[alkynylene]m-POLY forms, where POLY is a water-soluble polymer and n, m, and p are integers within the defined ranges.
Defined moieties and residue classes
X1 and X2 are independently selected from C(O) and N(R10)C(O); R10 is independently selected at each occurrence from hydrogen and the listed alkyl, alkenyl, alkynyl, carbocycle, heterocycle, and haloalkyl classes; Su is a hexose form of a monosaccharide; D is a drug moiety; and RL is a reactive group residue.
ROR1-binding antibody variable-region definitions
Some items additionally define isolated ROR1-binding antibodies by specific heavy-chain and light-chain CDR selections using SEQ ID NO ranges and variant rules.
The consolidated claim coverage is directed to an anti-ROR1 antibody conjugate that uses non-natural amino acids and is constrained by a Formula I scaffold. The inventive scope is defined by the L1 and Y linker system, R50 and optional R51 substitution, polymer-bearing linkers, and the included residue and moiety definitions for COMP, POLY, Su, D, and RL.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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