Humanized anti-prostate -specific membrane antigen (PSMA) antibody drug conjugates
Inventors
Bhowmik, Shivarupam • Wang, Jianing • Xia, Jinming • Brady, William • Tian, Feng
Assignees
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Publication Number
US-12059473-B2
Publication Date
2024-08-13
Expiration Date
Abstract
The invention relates to prostate specific membrane antigen humanized antibodies (anti-PSMA) and anti-PSMA antibody drug conjugates. The invention also relates to methods and compositions for using anti-PSMA antibody drug conjugates in inhibiting, preventing or treating PSMA related diseases or cancers.
Core Innovation
The invention provides humanized anti-prostate specific membrane antigen (anti-PSMA) antibody variants and anti-PSMA antibody drug conjugates comprising a humanized anti-PSMA antibody conjugated to at least one drug-linker. The anti-PSMA antibody includes heavy chain sequences selected from SEQ ID NOs: 8, 10, 12 and 14 and light chain sequences selected from SEQ ID NOs: 9, 11, 13 and 15, and conjugation occurs via a non-naturally encoded amino acid incorporated in the heavy chain sequence.
The disclosure further links these antibody variants to site-specific conjugation chemistry through non-naturally encoded amino acids, including para-acetyl phenylalanine. In a narrower embodiment, the anti-PSMA antibody comprises the heavy chain sequence of SEQ ID NO: 8 and the light chain sequence of SEQ ID NO: 9, and para-acetyl phenylalanine is incorporated at heavy chain position A114 according to Kabat numbering.
The at least one drug-linker comprises a cytotoxic agent, including dolastatin, dolastatin derivatives, or analogs, and the document also describes cleavable and non-cleavable/short linker chemistry together with representative drug-linker compounds and depicted chemical structures. The patent addresses PSMA-related cancers and diseases by providing anti-PSMA antibody and anti-PSMA ADC compositions for therapeutic and prophylactic use.
It further describes combination approaches, including combination with enzalutamide and immunostimulatory or immunomodulatory drugs, and references pharmacokinetics and tumor response in animal models, including mouse, rat, monkey, xenograft, and PDX prostate models.
Claims Coverage
The independent claims cover 4 inventive features: defined anti-PSMA antibody heavy and light chain sequence selections, heavy-chain incorporation of a non-naturally encoded amino acid, an ADC with a cytotoxic drug-linker via that amino acid, and a narrower para-acetyl phenylalanine embodiment at heavy-chain position A114.
Anti-psma antibody with specified heavy and light chain sequences
An anti-prostate specific membrane antigen (anti-PSMA) antibody comprising a heavy chain sequence selected from SEQ ID NOs: 8, 10, 12 and 14 and a light chain sequence selected from SEQ ID NOs: 9, 11, 13 and 15.
Anti-psma antibody with heavy-chain non-naturally encoded amino acid
An anti-prostate specific membrane antigen (anti-PSMA) antibody comprising a heavy chain sequence selected from SEQ ID NOs: 8, 10, 12 and 14 and a light chain sequence selected from SEQ ID NOs: 9, 11, 13 and 15, wherein the heavy chain sequence comprises a non-naturally encoded amino acid.
Anti-psma ADC with cytotoxic drug-linker via non-naturally encoded amino acid conjugation
An antibody drug conjugate comprising a humanized anti-prostate specific membrane antigen (anti-PSMA) antibody conjugated to at least one drug-linker, wherein the at least one drug-linker comprises a cytotoxic agent, wherein the anti-PSMA antibody comprises a heavy chain sequence selected from SEQ ID NOs: 8, 10, 12 and 14 and a light chain sequence selected from SEQ ID NOs: 9, 11, 13 and 15, and wherein the conjugation occurs via a non-naturally encoded amino acid incorporated in the heavy chain sequence.
Site-specific para-acetyl phenylalanine ADC at heavy-chain position A114
An antibody drug conjugate comprising an anti-prostate specific membrane antigen antibody conjugated to a drug-linker, wherein the conjugation occurs via a para-acetyl phenylalanine incorporated in the heavy chain sequence of the antibody, wherein the anti-PSMA antibody comprises the heavy chain sequence of SEQ ID NO: 8 and the light chain sequence of SEQ ID NO: 9, in which the para-acetyl phenylalanine is incorporated at heavy chain position A114 according to Kabat numbering, and wherein the drug-linker has the following structure.
Overall, the claims converge on site-specific anti-PSMA conjugation using a non-naturally encoded amino acid incorporated into a heavy chain defined by selected SEQ ID NOs, with an ADC embodiment requiring a cytotoxic agent via a drug-linker and a more specific embodiment that fixes para-acetyl phenylalanine at heavy-chain position A114 with heavy and light sequences SEQ ID NO: 8 and SEQ ID NO: 9.
Stated Advantages
increase anti-PSMA antibody/variant/ADC serum half-life
increase water solubility
increase bioavailability
increase therapeutic half-life
increase circulation time
modulate immunogenicity
Documented Applications
Treating a subject with a PSMA-expressing cancer cell or cancer by administering an effective amount of an antibody drug conjugate.
Reducing or inhibiting tumor growth or progression in a PSMA-expressing cancer or cancer cell by contacting it with an effective amount of the antibody drug conjugate.
Combination therapy including co-therapy with enzalutamide.
Co-administration of immunostimulatory agents or immunomodulators together with the disclosed treatment context.
A method to reduce or inhibit tumor growth or progression in a PSMA-expressing cancer or cancer cell by contacting it with an effective amount of the antibody drug conjugate.
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