Immunoconjugates targeting CD46 and methods of use thereof
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Publication Number
US-11484604-B2
Publication Date
2022-11-01
Expiration Date
Abstract
Disclosed herein are immunoconjugates comprising a CD46 binding domain and effector agent. Further provided herein are methods of treating cancer comprising administering to a subject having cancer a pharmaceutical composition comprising immunoconjugates comprising a CD46 binding domain and effector agent.
Core Innovation
The invention provides a pharmaceutical composition comprising an immunoconjugate, a pharmaceutically acceptable buffer, and a pharmaceutically acceptable stabilizing agent. The immunoconjugate comprises a recombinant antibody with specified heavy chain and light chain sequences and one, two, three or four pairs of adducts, each adduct including monomethylauristatin E (MMAE) conjugated to the recombinant antibody via a maleimidocaproyl-valine-citrulline-para-amino benzyloxycarbonyl (mc-vc-PAB) linker.
The adducts are conjugated to cysteine residues of the recombinant antibody, with the cysteine residues selected from C219, C214, C225, and C228 as recited. The composition further specifies about 20 mM histidine at about pH 6.0, about 0.01% polysorbate-80, and about 8.0% sucrose.
The described content supports the disclosed formulation and immunoconjugate design for FOR46, an immunoconjugate including YS5FL and MMAE via mc-vc-PAB. Stability evaluations include retained potency and binding after storage and reduced aggregation and visible particles, with stress testing used to support selection of sucrose and polysorbate-80.
The document further describes clinical dose-escalation programs for metastatic castration-resistant prostate cancer and relapsed or refractory multiple myeloma using the disclosed composition in an every-21-day intravenous dosing structure.
Claims Coverage
The independent claim is directed to a pharmaceutical composition with a defined MMAE immunoconjugate architecture and a defined buffer, stabilizer, and sucrose formulation. Two additional independent method-of-treatment claims administer the composition to specific oncology indications with defined intravenous dosing structures.
Pharmaceutical composition with mc-vc-PAB MMAE immunoconjugate and defined histidine, polysorbate-80, and sucrose formulation
A pharmaceutical composition comprising an immunoconjugate, a pharmaceutically acceptable buffer, and a pharmaceutically acceptable stabilizing agent, wherein the immunoconjugate comprises a recombinant antibody with specified first and second heavy chains and light chains, one to four pairs of adducts, each adduct having MMAE conjugated to the recombinant antibody via an mc-vc-PAB linker, each adduct conjugated to cysteine residue pairs selected from C219, C214, C225, and C228 configurations, and wherein the buffer is about 20 mM histidine at about pH 6.0, the stabilizing agent is about 0.01% polysorbate-80, and the composition comprises about 8.0% sucrose.
Intravenous treatment of metastatic castration-resistant prostate cancer with defined immunoconjugate dosing interval
A method of treating metastatic castration-resistant prostate cancer by administering the pharmaceutical composition intravenously at a dose of about 1.8 mg to about 3.0 mg of the immunoconjugate per kg of adjusted body weight every 21 days for at least three cycles.
Intravenous treatment of relapsed or refractory multiple myeloma with defined immunoconjugate dosing interval
A method of treating relapsed or refractory multiple myeloma by administering the pharmaceutical composition intravenously at a dose of about 1.2 mg to about 3.0 mg of the immunoconjugate per kg of adjusted body weight every 21 days for at least three cycles.
Overall coverage centers on the defined MMAE immunoconjugate architecture using the mc-vc-PAB linker and cysteine-targeted adduct conjugation, formulated in about 20 mM histidine at about pH 6.0 with about 0.01% polysorbate-80 and about 8.0% sucrose, and on intravenous every-21-day treatment methods for metastatic castration-resistant prostate cancer and relapsed or refractory multiple myeloma using the specified dose ranges.
Stated Advantages
Improved formulation stability outcomes are described, including retained binding and potency after storage and reduced aggregation and visible particles under stress testing.
The development and stress testing support selection of sucrose and polysorbate-80 for stability against thermal and agitation stresses.
Documented Applications
Treatment of metastatic castration-resistant prostate cancer using an intravenous dosing structure every 21 days with dose escalation and efficacy/toxicity outcomes described.
Treatment of relapsed or refractory multiple myeloma using an intravenous dose-escalation and expansion program with efficacy and safety/tolerability outcomes described.
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