Antibody-drug conjugates and immunotoxins
Inventors
Kontermann, Roland • Pfizenmaier, Klaus • Ferrer, Cristina • Fabre, Myriam • Simon, Laureano
Assignees
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Publication Number
US-10137202-B2
Publication Date
2018-11-27
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 disclosed invention provides hu36 anti-FAP IgG1 constructs that selectively bind fibroblast activation protein alpha (FAP). It includes detailed sequence definitions for the hu36 anti-FAP IgG1 heavy chain and light chain complementarity determining regions 1-3 (CDRH1-3 and CDRL1-3), and specifies both chimeric hu36-IgG1 and humanized hu36-IgG1 constructs. The disclosed hu36 antibody binding is characterized as strong, subnanomolar binding to recombinant and cell-surface FAP, including cross-reactivity to human and murine FAP.
The invention further discloses anti-FAP immunotoxins and cytolysin/tubulysin ADC payload-linker constructs using Nigrin-b A-chain (recNgA). It includes design and structural variants for a vcPABA linker positioned at cytolysin R1 versus R4, together with ethylene glycol spacer variants. The disclosed payload-linker constructs are characterized for conjugate properties, including DAR and SEC purity, and for effects such as microtubule inhibition and cytotoxicity trends.
The disclosed work culminates in FAP-specific in vivo efficacy results using the hu36:TAM conjugates in pancreas cancer PDX models. The document references FAP-specific conjugate constructs and evaluates efficacy in named PDX models including Panc185 PDX and PAXF-736 PDX. It also describes combination efficacy with Gemcitabine in the stated models.
Claims Coverage
The independent claims define two conjugate sets centered on an FAP-selective antibody linked to a cytolysin drug through a linker, with p = 1 to 10. One independent claim specifies the heavy chain and light chain complementarity determining regions 1-3 by sequence, and the other further restricts the L-D structure to a selected group.
FAP-selective antibody CDRH1-3 and CDRL1-3 linked to cytolysin drug with p = 1 to 10
A conjugate having formula I or a pharmaceutically acceptable salt or solvate, where A selectively binds fibroblast activation protein alpha (FAP) and comprises heavy chain complementarity determining regions 1-3 (CDRH1-3) and light chain complementarity determining regions 1-3 (CDRL1-3) having the specified amino acid sequences; L is a linker; D is a drug comprising a cytolysin; and p is 1 to 10.
Cytolysin conjugate with linker-drug structure selected from a defined group
A conjugate having formula I or a pharmaceutically acceptable salt or solvate, where A selectively binds fibroblast activation protein alpha (FAP), L is a linker, D is a drug comprising a cytolysin, and p is 1 to 10, and wherein L-D has a structure selected from the group consisting of a defined group.
Overall, the independent claims define an FAP-selective antibody conjugate with a cytolysin payload, linker attachment, and conjugation stoichiometry p = 1 to 10. The claims are distinguished by specified CDRH1-3/CDRL1-3 sequences in one claim set and by a defined L-D structural selection in the other.
Stated Advantages
Documented Applications
Treating tumors in a mammalian subject where the tumor and/or surrounding stroma expresses fibroblast activation protein alpha (FAP).
Treating an FAP-expressing tumor, including pancreatic cancer, breast cancer, melanoma, lung cancer, head and neck cancer, ovarian cancer, bladder cancer, or colon cancer.
Treating a fibroblast activation protein alpha (FAP)-expressing inflammatory condition in a mammalian subject.
Combination treatment with other antitumor drugs, including gemcitabine, Abraxane, bevacizumab, nivolumab, and pembrolizumab.
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