Methods of treating cancer with a combination of a platinum-based agent and an anti-tissue factor antibody-drug conjugate
Inventors
RANGWALA, RESHMA ABDULLA • BREIJ, Esther C. W. • Verploegen, Sandra • ABIDOYE, Oyewale O. • NICACIO, LEONARDO VIANA
Assignees
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Publication Number
US-12246025-B2
Publication Date
2025-03-11
Expiration Date
Abstract
The invention provides a platinum-based agent (e.g., carboplatin) in combination with an antibody-drug conjugate that binds to tissue factor (TF) (e.g., tisotumab vedotin) and their use in methods of treating cancer, such as bladder cancer and cervical cancer. The invention also provides compositions and kits comprising the platinum-based agent (e.g., carboplatin) and the antibody-drug conjugate that binds to TF (e.g., tisotumab vedotin) for use in treating cancer, such as bladder cancer and cervical cancer.
Core Innovation
The invention relates to a method of treating cancer in a subject by administering a platinum-based agent together with an antibody-drug conjugate that binds to tissue factor (TF). The antibody-drug conjugate comprises an anti-TF antibody or an antigen-binding fragment thereof conjugated to monomethyl auristatin E or monomethyl auristatin. In the disclosed embodiments, the anti-TF ADC includes tisotumab and tisotumab vedotin-based ADCs in combination with platinum-based agents.
The described ADC includes cleavable peptide linker embodiments connecting the anti-TF antibody or antigen-binding fragment to monomethyl auristatin E, with attachment to antibody sulfhydryl residues via partial or full reduction and an MC-vc-PAB cleavable peptide motif. The ADC is characterized by drug-load and analytical measurement, including distribution parameter p from 1 to 8, with an average around 4 in some embodiments, and measurement by hydrophobic interaction chromatography and reversed phase HPLC.
The combination treatment is framed with administration routes such as intravenous administration and sequential versus simultaneous administration. The disclosed platinum agents include carboplatin, cisplatin, oxaliplatin, and nedaplatin, and treatment outcomes are evaluated using tumor size reduction, RECIST v1.1 response endpoints, objective response rate, duration of response, time to response, progression-free survival, overall survival, and TF-expression thresholds based on TF-expressing tumor cell fraction.
Claims Coverage
The independent claim covers administering a platinum-based agent together with a TF-binding antibody-drug conjugate comprising an anti-TF antibody or antigen-binding fragment conjugated to monomethyl auristatin. The claim set is refined by dependent claims that add quantitative dosing constraints, specify particular anti-TF antibody embodiments, include linker and conjugation details, and impose TF-expression constraints and therapeutic-effect endpoints.
Platinum-based agent plus TF-binding MMAE ADC for treating cancer
A method of treating cancer in a subject by administering to the subject a platinum-based agent and an antibody-drug conjugate that binds to tissue factor (TF), wherein the antibody-drug conjugate comprises an anti-TF antibody or an antigen-binding fragment thereof conjugated to monomethyl auristatin or monomethyl auristatin E.
ADC dose range constraint
Administering the antibody-drug conjugate at a dose ranging from about 0.9 mg/kg to about 2.1 mg/kg.
Platinum exposure constraint by AUC
Administering the platinum-based agent at a dose with AUC between about 4 and about 6.
IMGT-defined CDR sequence specification for anti-TF antibody
The anti-TF antibody or antigen-binding fragment has heavy- and light-chain variable regions including IMGT-defined CDRs with SEQ ID NO:1-6 sequences.
Tisotumab as the anti-TF antibody
The anti-TF antibody of the antibody-drug conjugate is tisotumab.
MC-vc-PAB cleavable peptide linker with Ab-MC-vc-PAB-MMAE structures
The antibody-drug conjugate includes cleavable peptide linker embodiments connecting the anti-TF antibody or antigen-binding fragment to monomethyl auristatin E, with attachment to antibody sulfhydryl residues via partial or full reduction and an MC-vc-PAB cleavable peptide motif, forming Ab-MC-vc-PAB-MMAE with p from 1 to 8.
TF expression threshold in cervical cancer cells
At least about 0.1% up to at least about 80% of cervical cancer cells express TF.
The claim coverage centers on combination treatment using a platinum-based agent with a TF-binding MMAE ADC, with refinements that specify ADC dosing, platinum exposure by AUC, anti-TF antibody embodiments including tisotumab, linker and conjugation details, and a TF-expression threshold constraint for cervical cancer cells.
Stated Advantages
Improved therapeutic effects are described relative to baseline.
Ocular and adverse-event mitigation is described, including use of preservative-free lubricating eye drops and steroid or ocular vasoconstrictor drops.
Documented Applications
Phase II clinical trial for cervical cancer using combination therapy with a TF-binding ADC and a platinum-based agent, including administration-route and scheduling considerations and evaluation of therapeutic endpoints and adverse events such as conjunctivitis and keratitis.
Treating bladder cancer with a platinum-based chemotherapy agent combined with a TF-binding ADC using an anti-TF antibody conjugated to monomethyl auristatin.
Treating cervical cancer with a platinum-based chemotherapy agent combined with a TF-binding ADC using an anti-TF antibody conjugated to monomethyl auristatin.
Preclinical tumor activity evaluation using cisplatin/carboplatin combinations with tisotumab vedotin in xenograft mouse models.
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