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Genetic Encoding of a Non-Canonical Amino Acid for the Generation of Antibody-Drug Conjugates Through a Fast Bioorthogonal Reaction
Published on: September 14, 2018
Treating Tissue Factor-Positive Cancers with Antibody-Drug Conjugates That Do Not Affect Blood Clotting
Jan-Willem Theunissen1, Allen G Cai2, Maryam M Bhatti2
1Iconic Therapeutics, South San Francisco, California. jtheunissen@iconictherapeutics.com.
Abstract:
The primary function of tissue factor (TF) resides in the vasculature as a cofactor of blood clotting; however, multiple solid tumors aberrantly express this transmembrane receptor on the cell surface. Here, we developed anti-TF antibody-drug conjugates (ADC) that did not interfere with the coagulation cascade and benchmarked them against previously developed anti-TF ADCs. After screening an affinity-matured antibody panel of diverse paratopes and affinities, we identified one primary paratope family that did not inhibit conversion of Factor X (FX) to activated Factor X (FXa) and did not affect conversion of prothrombin to thrombin. The rest of the antibody panel and previously developed anti-TF antibodies were found to perturb coagulation to varying degrees. To compare the anticancer activity of coagulation-inert and -inhibitory antibodies as ADCs, a selection of antibodies was conjugated to the prototypic cytotoxic agent monomethyl auristatin E (MMAE) through a protease-cleavable linker. The coagulation-inert and -inhibitory anti-TF ADCs both killed cancer cells effectively. Importantly, the coagulation-inert ADCs were as efficacious as tisotumab vedotin, a clinical stage ADC that affected blood clotting, including in patient-derived xenografts from three solid tumor indications with a need for new therapeutic treatments-squamous cell carcinoma of the head and neck (SCCHN), ovarian, and gastric adenocarcinoma. Furthermore, a subset of the anti-TF antibodies could also be considered for the treatment of other diseases associated with upregulation of membranous TF expression, such as macular degeneration. Mol Cancer Ther; 17(11); 2412-26. ©2018 AACR.
Insights
New antibody-drug conjugates targeting tissue factor (TF) show potent anticancer activity without disrupting blood clotting. These novel agents are as effective as existing therapies in preclinical models of solid tumors.
Area of Science:
- Oncology
- Hematology
- Immunology
Background:
- Tissue factor (TF) is a transmembrane receptor crucial for blood clotting, but is aberrantly expressed on multiple solid tumors.
- Existing anti-TF antibody-drug conjugates (ADCs) can interfere with the coagulation cascade, posing a clinical challenge.
Purpose of the Study:
- To develop novel anti-TF ADCs that are "coagulation-inert" and do not affect blood clotting.
- To compare the anticancer efficacy of coagulation-inert anti-TF ADCs with previously developed anti-TF ADCs that perturb coagulation.
Main Methods:
- Screening of an affinity-matured antibody panel to identify paratopes that do not inhibit key coagulation factors (FX, prothrombin).
- Conjugation of selected antibodies to monomethyl auristatin E (MMAE) via a protease-cleavable linker to create ADCs.
- Evaluation of anti-TF ADCs' anticancer activity in vitro and in patient-derived xenografts (PDX) of squamous cell carcinoma of the head and neck (SCCHN), ovarian, and gastric adenocarcinoma.
Main Results:
- Identified a paratope family of antibodies that did not inhibit Factor X or prothrombin conversion, thus remaining "coagulation-inert".
- Both coagulation-inert and -inhibitory anti-TF ADCs demonstrated effective cancer cell killing in vitro.
- Coagulation-inert anti-TF ADCs exhibited comparable efficacy to tisotumab vedotin in preclinical solid tumor models, including SCCHN, ovarian, and gastric cancers.
Conclusions:
- Developed novel, coagulation-inert anti-TF ADCs with significant anticancer potential.
- These ADCs offer a promising therapeutic strategy for solid tumors without compromising hemostasis.
- Anti-TF antibodies may also be relevant for treating other diseases with upregulated membranous TF expression, such as macular degeneration.
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