Protein-polymer-drug conjugates
Inventors
Smith, Roger A. • Damle, Nitin K. • Yurkovetskiy, Aleksandr V. • YIN, Mao • Lowinger, Timothy B. • Thomas, Joshua D. • STEVENSON, Cheri A. • Gurijala, Venu R.
Assignees
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Publication Number
US-11434278-B2
Publication Date
2022-09-06
Expiration Date
Abstract
A polymeric scaffold useful for conjugating with a protein based recognition-molecule (PBRM) to form a PBRM-polymer-drug conjugate is described herein. The scaffold includes one or more terminal maleimido groups. Also disclosed is a PBRM-polymer-drug conjugate prepared from the scaffold. Compositions comprising the conjugates, methods of their preparation, and methods of treating various disorders with the conjugates or their compositions are also described.
Core Innovation
The invention relates to a therapeutic drug and targeting conjugate useful in anti-neoplastic therapies. The conjugate comprises an anti-5T4 ligand and a poly(1-hydroxymethylethylene hydroxymethyl-formal) (PHF) polymeric scaffold, where the anti-5T4 ligand is an immunoglobulin or functional fragment comprising an anti-5T4 scFvFc and the construct is designated as SEQ ID NO: 7. The sulfur atom is part of the single chain antibody construct.
The PHF polymeric scaffold comprises units that may be randomly connected to each other and has a molecular weight ranging from about 2 kDa to about 40 kDa. The average polymeric scaffold to anti-5T4 single chain antibody ratio is about 2:1 to about 4:1, and the auristatin F HPA to anti-5T4 antibody ratio is about 8:1 to about 13:1.
The subject matter further includes pharmaceutically acceptable carrier formulations and multiple example structures of antibody-drug conjugates using PHF-based scaffolds and anti-5T4 scFvFc targeting. The document also states that the invention is for treating cancer in a subject, with the treated cancer selected from an enumerated group of specific cancer types.
Claims Coverage
The consolidated claim coverage centers on one independent therapeutic drug and targeting conjugate claim, with dependent claims adding pharmaceutical composition and cancer treatment scope. The inventive content is organized around anti-5T4 scFvFc targeting, a PHF polymeric scaffold, and defined scaffold-to-antibody and auristatin F HPA-to-antibody ratios.
Anti-5T4 scFvFc ligand defined by SEQ ID NO: 7
An anti-5T4 ligand comprising an immunoglobulin or functional fragment that is an anti-5T4 scFvFc, wherein the single chain antibody construct comprises the amino sequence designated as SEQ ID NO: 7 and the sulfur atom is part of the single chain antibody construct.
PHF polymeric scaffold with randomly connected units and defined molecular weight
A poly(1-hydroxymethylethylene hydroxymethyl-formal) (PHF) polymeric scaffold comprising units that may be randomly connected to each other, wherein the PHF has a molecular weight ranging from about 2 kDa to about 40 kDa.
Specified scaffold-to-antibody ratio
The average polymeric scaffold to anti-5T4 single chain antibody ratio is about 2:1 to about 4:1.
Specified auristatin F HPA-to-antibody ratio
The auristatin F HPA to anti-5T4 antibody ratio is about 8:1 to about 13:1.
Pharmaceutically acceptable carrier
A pharmaceutical composition comprising the therapeutic drug and targeting conjugate and a pharmaceutically acceptable carrier.
Cancer treatment by administering an effective amount
A method for treating cancer in a subject in need by administering an effective amount of the pharmaceutical composition.
Treatment restricted to enumerated cancer types
The cancer is selected from a listed group of specific cancer types.
Overall, the claims cover an anti-neoplastic therapeutic drug and targeting conjugate in which an anti-5T4 scFvFc defined by SEQ ID NO: 7 is linked to a PHF polymeric scaffold with specified molecular weight and loading ratios. Dependent claims extend the scope to pharmaceutical composition and methods of treating cancer, including treatment of enumerated cancer types.
Stated Advantages
Improved bioavailability.
Maintained efficacy with higher drug load.
Improved thiol-conjugation stability.
Documented Applications
Anti-neoplastic therapies.
Treating cancer in a subject.
Treatment of cancer selected from anal, astrocytoma, leukemia, lymphoma, head and neck, liver, testicular, cervical, sarcoma, hemangioma, esophageal, eye, laryngeal, mouth, mesothelioma, skin, myeloma, oral, rectal, throat, bladder, breast, uterus, ovary, prostate, lung, colon, pancreas, renal, and gastric cancers.
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