Antibody-drug conjugates and immunotoxins
Inventors
Kontermann, Roland • Pfizenmaier, Klaus • Ferrer, Cristina • Fabre, Myriam • Simon, Laureano
Assignees
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Publication Number
US-10864278-B2
Publication Date
2020-12-15
Expiration Date
Abstract
The present invention relates to conjugates, in particular antibody-drug conjugates and immunotoxins, having the formula I: A-(L-D)p (I) or a pharmaceutically acceptable salts or solvates thereof, wherein: A is an antibody that selectively binds FAP; L is a linker; D is a drug comprising a cytolysin or a Nigrin-b A-chain; and p is 1 to 10, and to use of such conjugates in the therapeutic treatment of tumors. Methods of producing such conjugates and components for use in such methods are disclosed.
Core Innovation
The invention relates to an antibody-drug conjugate having formula I, where A is an antibody that selectively binds fibroblast activation protein (FAP), L is a linker comprising a spacer, and D is a drug comprising a cytolysin. The conjugate is provided as the conjugate itself or as a pharmaceutically acceptable salt or solvate thereof, with p defined as 1 to 10.
The antibody components are described as anti-FAP hu36 IgG1 and humanized or chimeric variants, including specified VH and VL domains and CDRH1-3 and CDRL1-3 regions with SEQ ID NOs. The described antibody variants include ADCC/CDC deficiency mutations and a glycosylation site N297, and the patent content further reports binding to recombinant FAP and FAP-expressing cells, cross-reactivity to human and murine FAP, and internalization.
The invention also covers cytolysin-based immunotoxin and ADC constructions using cytolysin derivatives and linker derivatives, including vcPABA-linker derivatives, conjugated to the anti-FAP hu36 antibody to form ADCs. The documented evaluation includes microtubule inhibition and cytotoxicity measurements, as well as ADC chemical characterization including DAR and aggregation, target binding/internalization, and in vivo efficacy in patient-derived xenograft pancreas cancer models with differentiation based on linker position/spacer length.
Claims Coverage
The partial content includes two independent claim sets, for a total of two independent claims. Across these independent claims, the coverage is anchored on an FAP-selective antibody (A), a linker (L), and a cytolysin-type drug (D) incorporated into formula I, with p constrained to 1 to 10.
FAP-selective antibody-linker-cytolysin conjugate (formula I with cytolysin structural variables)
A conjugate having formula I where A is an antibody that selectively binds FAP, L is a linker comprising a spacer, D is a drug comprising a cytolysin with specified structural variables, and the conjugate is provided as a conjugate or a pharmaceutically acceptable salt or solvate thereof, with p defined as 1 to 10.
FAP-selective antibody-linker-drug conjugate (formula I with p defined as 1 to 10)
A conjugate having formula I where A is an antibody that selectively binds FAP, L is a linker, D is a drug having the structure as recited, and the conjugate is provided as a conjugate or a pharmaceutically acceptable salt or solvate thereof, with p defined as 1 to 10.
Overall, the independent-claim coverage centers on antibody-drug conjugates that use an antibody selectively binding FAP, coupled via a linker to a cytolysin-type drug within formula I, with p constrained to 1 to 10; one independent claim further specifies the cytolysin structure variables in the drug definition.
Stated Advantages
Targets fibroblast activation protein alpha (FAP) using an antibody that selectively binds FAP.
Supports therapeutic cytotoxicity by delivering a cytolysin (cytolysin of formula IV) payload via an antibody-drug conjugate.
Supports use in combination with antitumor drugs including immune checkpoint inhibitors (anti-PD-1/PD-L1).
Documented Applications
Therapeutic use for tumors, including solid tumors such as pancreatic, breast, melanoma, lung, head & neck, ovarian, bladder, and colon.
Therapeutic use for FAP-expressing inflammatory conditions, including rheumatoid arthritis.
Combination therapeutic use with agents including gemcitabine/Abraxane and bevacizumab, and immune checkpoint inhibitors including anti-PD-1/PD-L1.
In vivo efficacy in patient-derived xenograft (PDX) pancreas cancer models is documented for cytolysin-linker ADC candidates with differentiation based on linker position/spacer length.
Evaluation of targeting includes binding to recombinant FAP and FAP-expressing cells and internalization, supporting application to FAP-expressing contexts.
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