Anti-5T4 antibodies and antibody-drug conjugates
Inventors
Van Der Lee, Miranda Maria Cornelia • Ariaans, Gerardus Joseph Andreas • SCHOUTEN, Jan • Blomenrohr, Marion • GROOTHUIS, Patrick Gerhard • Coumans, Rudy Gerardus Elisabeth
Assignees
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Publication Number
US-11584801-B2
Publication Date
2023-02-21
Expiration Date
Abstract
The present invention relates to antibodies against the human 5T4 oncofoetal antigen and corresponding antibody-drug conjugates that are suitable for testing in clinical trials. The antibodies are cross-reactive for humans and cynomolgus monkeys and exhibit an affinity for human 5T4 antigen which is in the same order of magnitude as their affinity for cynomolgus monkey 5T4 antigen. The invention further relates to the use of the antibodies and corresponding ADCs in the treatment of solid tumours and haematological malignancies.
Core Innovation
The disclosed invention relates to antibody-drug conjugates (ADC) comprising an anti-5T4 antibody conjugated to a linker drug, for treating a human solid tumor or a haematological malignancy. The anti-5T4 antibody is characterized by heavy chain (HC) and light chain (LC) variable region (VR) complementarity determining regions (CDRs) selected from specified CDR sets shown in multiple SEQ ID NOs.
The invention further specifies that the linker drug is conjugated to the anti-5T4 antibody in a site-specific manner using engineered cysteine. The engineered cysteine positions are described in relation to native interchain disulfide cysteines, with stated preferences for heavy chain position 41 and light chain positions 40 and 41 (Kabat numbering), thereby enabling ADC conjugation while preserving binding and reducing hydrophobicity and protease-triggered premature drug release.
The ADC is defined using structural formulas (I) and (II) and conjugate parameters, including n and average DAR (m), with stated preferred ranges. The linker drug is particularly described as duocarmycin derivatives, and the disclosure includes that site-specific vc-seco-DUBA ADCs maintain affinity and show improved hydrophobicity behavior and enhanced potency/efficacy and pharmacokinetics versus a prior art H8-vc-seco-DUBA control.
Claims Coverage
The patent contains one independent claim covering a method of treating specific human cancers with an ADC defined by an anti-5T4 antibody having CDRs selected from multiple SEQ ID NO sets, and a linker-drug conjugate. The dependent claims refine the independent claim by specifying conjugate/ADC structural formulas, conjugation constraints (including engineered cysteine), quantitative conjugate ranges, particular antibody CDR/sequence sets, and defined cytotoxic drug classes for the linker drug.
Treating a human solid tumor or haematological malignancy with an anti-5T4 ADC
Administering an effective amount of an antibody-drug conjugate (ADC) to treat a human solid tumor or a haematological malignancy, where the ADC comprises an anti-5T4 antibody having a linker drug conjugated thereto.
Anti-5T4 CDR sets selected from SEQ ID NO-defined groups
Selecting the antibody heavy chain (HC) and light chain (LC) variable region (VR) complementarity determining regions (CDRs) from the group consisting of CDR sets shown in SEQ ID NO:1/2, SEQ ID NO:5/6, SEQ ID NO:7/8, SEQ ID NO:11/12, SEQ ID NO:13/14, SEQ ID NO:17/18, SEQ ID NO:19/20, and SEQ ID NO:25/26.
Site-specific conjugation via engineered cysteine
Conjugating the linker drug to the antibody at least through an engineered cysteine.
ADC defined by structural formulas (I) and (II) with conjugate constraints
Using an ADC according to conjugate/ADC structural definitions that include values for n and m (average DAR), including the range n=0-3 and m as an average DAR from 1 to 6, as constrained by the structural formulas (I) and (II).
Linker drug comprises defined cytotoxic drug classes
Defining the linker drug as comprising a cytotoxic drug selected from duocarmycins, calicheamicins, pyrrolobenzodiazepine dimers, maytansinoids, and auristatins.
Overall, the claim set focuses on treating cancer with an anti-5T4 ADC where the anti-5T4 antibody is defined by specific SEQ ID NO-based CDR selections, and the ADC is further constrained by site-specific conjugation using engineered cysteine and by ADC structural/conjugate parameters, with the linker drug selected from specified cytotoxic drug classes.
Stated Advantages
Maintains affinity for engineered site-specific vc-seco-DUBA ADCs.
Improved hydrophobicity (as indicated by HIC retention behavior).
Enhanced potency/efficacy versus prior art H8-vc-seco-DUBA.
Enhanced pharmacokinetics versus prior art H8-vc-seco-DUBA.
Documented Applications
Treating a human solid tumor.
Treating a haematological malignancy.
Example solid tumors explicitly listed include breast cancer, gastric cancer, colorectal cancer, ovarian cancer, lung cancer and mesothelioma.
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