Anti-folate receptor alpha antibody conjugated with hemiasterlins
Inventors
Stafford, Ryan • Yam, Alice • Li, Xiaofan • Yin, Gang • Kline, Toni • Abrahams, Cristina • De Almeida, Venita
Assignees
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Publication Number
US-12071477-B2
Publication Date
2024-08-27
Expiration Date
Abstract
The present disclosure relates to antibody conjugates with binding specificity for folate receptor alpha (FOLR1) and its isoforms and homologs, and compositions comprising the antibody conjugates, including pharmaceutical compositions. The variable light chains are those of trastuzumab. Also provided are methods of producing the antibody conjugates and compositions as well as methods of using the antibody conjugates and compositions, such as in therapeutic and diagnostic methods. The antibody conjugates comprise a non-natural amino acid at a site selected from the group consisting of HC-F404, HC-K121, HC-Y180, HC-F241, HC-221, LC-T22, LC-S7, LC-N152, LC-K42, LC-E161, LC-D170, HC-S136, HC-S25, HC-A40, HC-S119, HC-S190, HC-K222, HC-R19, HC-Y52, or HC-S70, according to the Kabat, Chothia, or EU numbering scheme.
Core Innovation
The invention provides an antibody conjugate comprising an antibody that specifically binds to folate receptor alpha (FOLR1) linked site-specifically to at least one payload moiety, where the antibody conjugate is a compound according to formula E1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. The formula framework includes Ar, L, X with W1 through W5, EG, optional release trigger groups RT, HP, SG, R, and COMP as a residue of an antibody chain of FOLR1.
The antibody comprises three heavy chain CDRs and three light chain CDRs from one of the specified V_H/V_L pairs identified by SEQ ID NOs. The payload moiety is linked site-specifically by one or more non-natural amino acids, with disclosed embodiments including optional eliminator groups, hydrophilic group and spacer group definitions, and related conjugation chemistries.
The patent also specifies embodiments in which the payload moiety is a hemiasterlin residue. Additional disclosure includes representative linkage motifs and structural variants, including a triazole ring, a fused bicyclic nitrogen-containing ring, a sulfur linkage, and an oxime linkage.
Claims Coverage
The independent claims center on two inventive features: a site-specifically linked anti-FOLR1 antibody conjugate defined by formula E1, and a related anti-FOLR1 conjugate in which the payload moiety is a hemiasterlin residue. Both require linkage through one or more non-natural amino acids and CDR-defined antibody sequence sets.
Site-specific anti-FOLR1 antibody conjugate defined by formula E1
An antibody conjugate comprising an antibody that specifically binds to folate receptor alpha (FOLR1) linked site-specifically to at least one payload moiety, wherein the antibody conjugate is a compound according to formula E1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, with Ar, L, X, EG, RT, HP, SG, R, and COMP defined within the formula framework, and wherein the antibody comprises three heavy chain CDRs and three light chain CDRs from one of the specified V_H/V_L pairs and is linked site-specifically by one or more non-natural amino acids.
Hemiasterlin payload in site-specific anti-FOLR1 conjugate
An antibody conjugate comprising an antibody that specifically binds to folate receptor alpha (FOLR1) linked site-specifically to at least one payload moiety, wherein the payload moiety is a hemiasterlin residue, and wherein the antibody comprises three heavy chain CDRs and three light chain CDRs from one of the specified V_H/V_L pairs, linked site-specifically to at least one payload moiety by one or more non-natural amino acids.
Overall, the claims are directed to an anti-FOLR1 antibody conjugate linked site-specifically to a payload moiety by one or more non-natural amino acids, with one claim defined by the formula E1 framework and the other narrowing the payload to a hemiasterlin residue.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Preclinical evaluation of FOLR1-targeting antibody-drug conjugates including in vitro cytotoxicity comparisons in FOLRα-high versus moderate/heterogeneous models and in vivo tumor growth inhibition/regression in KB, Igrov1, and OVCAR3 models.
Specificity assessment including binding and cytotoxicity assays showing limited cross-reactivity to FOLRβ.
Pharmaceutical composition including the antibody conjugate and a pharmaceutically acceptable excipient, carrier, or diluent.
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