Anti-folate receptor antibody conjugates, compositions comprising anti-folate receptor antibody conjugates, and methods of making and using anti-folate receptor antibody conjugates
Inventors
Stafford, Ryan • Yam, Alice • Li, Xiaofan • Yin, Gang • Kline, Toni • Abrahams, Cristina • De Almeida, Venita
Assignees
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Publication Number
US-12427201-B2
Publication Date
2025-09-30
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. 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.
Core Innovation
The disclosed invention relates to site-specific antibody-drug conjugates comprising an IgG-class antibody that specifically binds folate receptor alpha (FOLR1) linked site-specifically to at least one payload moiety. The antibody comprises specified heavy-chain and light-chain CDR combinations. Disclosed conjugate features include non-natural amino-acid attachment sites, linker architectures with release triggers, eliminators, hydrophilic and spacer groups, and payloads including maytansines, hemiasterlins, amanitins, MMAF, and MMAE.
The content describes conjugates including cleavable hemiasterlin Conjugate P, with one independent claim specifying Conjugate P wherein n is an integer from 1 to 6. Antitumor evaluations demonstrate selective cytotoxicity against target-expressing cells and tumor-growth reduction across Igrov1, OVCAR3, KB cervical carcinoma, and patient-derived xenograft models. Because background sections are not included, the problem being solved is not explicitly described in the patent.
Claims Coverage
The independent claims cover two inventive features directed to site-specifically linked IgG antibody conjugates comprising specified CDR combinations.
Site-specifically payload-linked FOLR1-binding IgG antibody
The independent claim covers an IgG-class antibody that specifically binds FOLR1 and is linked site-specifically to at least one payload moiety, wherein the antibody comprises one of the recited heavy-chain and light-chain CDR combinations.
Site-specifically linked conjugate P structure
The independent claim covers an IgG-class antibody conjugate comprising one of the recited heavy-chain and light-chain CDR combinations, linked site-specifically to at least one payload moiety, and having the structure of Conjugate P, wherein n is an integer from 1 to 6.
The independent claims cover specified site-specifically payload-linked IgG antibody conjugates with defined CDR combinations, requiring either specific binding to FOLR1 or the defined Conjugate P chemical structure.
Stated Advantages
The antibody-drug conjugates exhibit potent, selective cytotoxicity toward FOLR1-expressing cells with little activity against FOLR2-expressing cells, as well as reduced tumor growth and delayed progression in FOLR1-positive xenograft and tumor models, while showing little or no significant effect in FOLR1-negative models.
Combination treatment of the antibody-drug conjugate with carboplatin or avelumab shows enhanced efficacy, tumor control, survival, or tumor-growth inhibition compared to single-agent administration in reported models.
The antibody-drug conjugate retained its drug-antibody ratio in plasma studies, displaying greater stability and less P-glycoprotein-mediated efflux liability compared to a comparator conjugate.
Reported mouse xenograft evaluations demonstrate reduced tumor growth relative to vehicle across several conjugates, including marked tumor-growth suppression by ADC Mol 1 in the KB model alongside generally modest treatment-associated body-weight changes.
Documented Applications
Therapeutic, diagnostic, analytical delivery, and affinity-purification applications utilizing FOLR1-binding antibody conjugates.
Treatment of triple-negative breast cancer, ovarian cancer, or endometrial cancer.
Antitumor evaluation in KB cervical carcinoma, Igrov1 ovarian cancer, OVCAR3, and FOLR1-positive and FOLR1-negative patient-derived xenograft models, administered alone or in combination with carboplatin or avelumab.
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