High turnover of tissue factor enables efficient intracellular delivery of antibody-drug conjugates.
Antibody-drug conjugates (ADC) are emerging as powerful cancer treatments that combine antibody-mediated tumor targeting with the potent cytotoxic activity of toxins. We recently reported the development of a novel ADC that delivers the cytotoxic payload monomethyl auristatin E (MMAE) to tumor cells expressing tissue factor (TF). By carefully selecting a TF-specific antibody that interferes with TF:FVIIa-dependent intracellular signaling, but not with the procoagulant activity of TF, an ADC was developed (TF-011-MMAE/HuMax-TF-ADC) that efficiently kills tumor cells, with an acceptable toxicology profile. To gain more insight in the efficacy of TF-directed ADC treatment, we compared the internalization characteristics and intracellular routing of TF with the EGFR and HER2. Both in absence and presence of antibody, TF demonstrated more efficient internalization, lysosomal targeting, and degradation than EGFR and HER2. By conjugating TF, EGFR, and HER2-specific antibodies with duostatin-3, a toxin that induces potent cytotoxicity upon antibody-mediated internalization but lacks the ability to induce bystander killing, we were able to compare cytotoxicity of ADCs with different tumor specificities. TF-ADC demonstrated effective killing against tumor cell lines with variable levels of target expression. In xenograft models, TF-ADC was relatively potent in reducing tumor growth compared with EGFR- and HER2-ADCs. We hypothesize that the constant turnover of TF on tumor cells makes this protein specifically suitable for an ADC approach.
Genmab, Utrecht, the Netherlands. BGO@genmab.com.
Bart E C G
BE
de Goeij
Genmab, Utrecht, the Netherlands.
David
D
Satijn
Genmab, Utrecht, the Netherlands.
Claudia M
CM
Freitag
Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands.
Richard
R
Wubbolts
Genmab, Utrecht, the Netherlands.
Wim K
WK
Bleeker
Concortis Biosystems Corp., San Diego, California.
Alisher
A
Khasanov
Concortis Biosystems Corp., San Diego, California.
Tong
T
Zhu
Concortis Biosystems Corp., San Diego, California.
Gary
G
Chen
Concortis Biosystems Corp., San Diego, California.
David
D
Miao
Genmab, Utrecht, the Netherlands.
Patrick H C
PH
van Berkel
Genmab, Utrecht, the Netherlands. Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
Paul W H I
PW
Parren
D000818:Animals; D000906:Antibodies; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D017209:Apoptosis; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism*; D015942:Factor VIIa / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000906:Antibodies; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D015942:Factor VIIa; D000922:Immunotoxins; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human