Non‐internalizing antibody–drug conjugates display potent anti‐cancer activity upon proteolytic release of monomethyl auristatin E in the subendothelial extracellular matrix

Abstract

Antibody-drug conjugates (ADCs) represent a promising class of biopharmaceuticals with the potential to localize at the tumor site and improve the therapeutic index of cytotoxic drugs. While it is generally believed that ADCs need to be internalized into tumor cells in order to display optimal therapeutic activity, it has recently been shown that non-internalizing antibodies can efficiently liberate disulfide-linked drugs at the extracellular tumor site, leading to potent anti-cancer activity in preclinical animal models. Here, we show that engineered variants of the F16 antibody, specific to a splice isoform of tenascin-C, selectively localize to the subendothelial tumor extracellular matrix in three mouse models of human cancer (U87, A431, MDA-MB-231). A site-specific coupling of F16 in IgG format with a monomethyl auristatin E (MMAE) derivative, featuring a valine-citrulline dipeptide linker equipped with a self-immolative spacer, yielded an ADC product, which cured tumor-bearing mice at a dose of 7 mg/Kg. The observation of an efficient extracellular proteolytic cleavage of the valine-citrulline linker was surprising, as it has generally been assumed that this peptidic structure would be selectively cleaved by cathepsin B in intracellular compartments. The products described in this article may be useful for the treatment of human malignancies, as their cognate antigen is strongly expressed in the majority of human solid tumors, lymphomas and aggressive leukemias, while being virtually undetectable in most normal adult tissues.

Ein Fest der Wissenschaft inmitten der Natur: Die 54. Bürgenstock‐Konferenz

“…Seine Gruppe beschäftigt sich intensiv mit der Herstellung und dem Engineering vollständig menschlicher Antikörperprodukte zur Therapie von Krebs und chronischen Entzündungen. Die antikörperbasierte selektive Zufuhr von immunstimulierenden Wirkstoffen an die Tumorstelle ist für therapeutische Anwendungen außerordentlich attraktiv, da sie die Kraft des Immunsystems nutzen und mit anderen Anti‐Krebs‐Modalitäten kombiniert werden können. Er gab auch Einblicke in die Erzeugung großer kodierter kombinatorischer Bibliotheken von Antikörpern und kleinen organischen Molekülen (DNA‐kodierte Chemie), sowie in die ligandenbasierte Abgabe von zytotoxischen Wirkstoffen an solide Tumore (niedermolekulare Wirkstoffkonjugate) …”

A Celebration of Science amidst Nature: The 54th Bürgenstock Conference

“…His group has been extensively working on the generation and engineering of fully human antibody products for the therapy of cancer and of chronic inflammatory conditions. The antibody‐based selective delivery of immunostimulatory agents to the tumor site is exceptionally attractive for therapeutic applications, since they exploit the power of the immune system and as they can be combined with other anti‐cancer modalities. He also gave insights into the generation of large encoded combinatorial libraries of antibodies and of small organic molecules (DNA‐encoded chemistry), as well as the ligand‐based delivery of cytotoxic agents to solid tumors (small molecule–drug conjugates) …”

“…Thesecond lecture on Monday morning was presented by Prof.D ario Neri (ETH Zürich) entitled "from encoded combinatorial libraries to targeted therapeutics", followed by extensive discussions.H eg uided us through on the topic of encoded libraries [10] and on encoded strategies such as singleand dual-pharmacophore libraries.H ep ointed out the limitations of conventional cancer chemotherapy and described additional possibilities,s uch as targeting tumors with small organic ligands. [11] His group has been extensively working on the generation and engineering of fully human antibody products for the therapy of cancer and of chronic inflammatory conditions.T he antibody-based selective delivery [12] of immunostimulatory agents to the tumor site is exceptionally attractive for therapeutic applications,s ince they exploit the power of the immune system and as they can be combined with other anti-cancer modalities.Healso gave insights into the generation of large encoded combinatorial libraries of antibodies and of small organic molecules (DNAencoded chemistry), [10a] as well as the ligand-based delivery of cytotoxic agents to solid tumors (small molecule-drug conjugates). [11b] Monday afternoon continued with chemical biology.Prof.…”

Targeting the extracellular matrix for delivery of bioactive molecules to sites of arthritis

“…The tumour‐associated ECM marker TenC is also becoming increasingly associated with RA (Schwenzer et al, ). The antibody F16 has been employed to target domain A1 of TenC and was efficacious at treating glioblastoma and carcinomas when conjugated to the cytotoxic agent monomethyl auristatin E via a labile valine‐citrulline dipeptide (Gébleux et al, ). TenC is also associated with adenocarcinomas, squamous cell carcinomas of the lung and cancer‐associated fibroblasts (CAFs) in the stroma.…”