Anti-Human Tissue Factor (TF) (Tisotumab) – Fc Muted™

TF-ECDHis and/or TF-expressing NSO cells

This biosimilar antibody is aseptically packaged and formulated in 0.01 M phosphate buffered saline (150 mM NaCl) PBS pH 7.2 - 7.4 with no carrier protein, potassium, calcium or preservatives added. Due to inherent biochemical properties of antibodies, certain products may be prone to precipitation over time. Precipitation may be removed by aseptic centrifugation and/or filtration.

Liquid

Recombinant biosimilar antibodies are manufactured in an animal free facility using only in vitro protein free cell culture techniques and are purified by a multi-step process including the use of protein A or G to assure extremely low levels of endotoxins, leachable protein A or aggregates.

To protect mouse colonies from infection by pathogens and to assure that experimental preclinical data is not affected by such pathogens, all of Leinco’s recombinant biosimilar antibodies are tested and guaranteed to be negative for all pathogens in the IDEXX IMPACT I Mouse Profile.

Functional grade preclinical antibodies may be stored sterile as received at 2-8°C for up to one month. For longer term storage, aseptically aliquot in working volumes without diluting and store at ≤ -70°C. Avoid Repeated Freeze Thaw Cycles.

Research Use Only

2 – 8° C Wet Ice

This non-therapeutic biosimilar antibody uses the same variable region sequence as the therapeutic antibody Tisotumab. GCT1015-04 (Tisotumab) is an antibody-drug conjugate composed of a fully human monoclonal antibody against tissue factor (TF) conjugated to monomethyl auristatin E (MMAE), a microtubule inhibitor.

Tissue factor (TF; also known as thromboplastin, factor III, or CD142) is the primary initiator of blood coagulation¹. During coagulation, TF interacts with proteolytic cleavage factor VII to generate activated FVII (FVIIa), which then forms a TF:FVIIa complex 2². This complex then activates coagulation factor X to generate FXa and ultimately leads to clot formation via thrombin. The coagulation cascade is initiated when a vessel wall is disrupted by injury or when TF is upregulated on monocytes due to inflammation. In either circumstance, TF is exposed to circulating FVII and FVIIa allowing clot formation to commence along with induction of intracellular protease-activated receptor 2 (PAR-2) signaling. TF contributes to tumor progression in a variety of cancers by exploiting both tissue factor procoagulant activity and PAR-2 signaling cascades. As such, TF is a target of cancer immunotherapy.

GCT1015-04 (Tisotumab) was developed to target TF-expressing tumors for the treatment of cervical and other cancers^1,2. Tisotumab delivers a toxic payload to tumor cells via its anti-TF humanized monoclonal antibody (TF-011) conjugated to the microtubule-disrupting agent MMAE. TF-011 is conjugated with maleimidocaproyl-valine-citrulline-p-aminobenzoyl- monomethyl auristatin E (vcMMAE) on cysteine groups in the antibody hinge region. MMAE initiates cell cycle arrest and apoptosis of both tumor and bystander cells upon delivery.

Tisotumab induces immunogenic cell death as well as antibody-dependent cellular toxicity and antibody-dependent cellular phagocytosis^1,2. Tisotumab also inhibits TF from binding FVIIa, and thereby inhibits TF:FVIIa-induced ERK phosphorylation and IL-8 production. Thus, PAR-2 dependent signaling is inhibited by the antigen-binding fragment. Tisotumab activity does not disrupt normal coagulation.

Tisotumab was generated by immunizing HuMAb mice with TF-ECDHis and/or TF-expressing NSO cells². Hybridomas were generated from mice that showed TF-specific antibodies in serum. The immunoglobulin variable heavy and light chain regions were sequenced, and recombinant antibodies were generated.

This non-therapeutic biosimilar antibody is not conjugated to MMAE and thus does not include the drug payload.

TF is expressed on the surface of cells from a wide variety of organs including, the brain, heart, intestine, kidney, lung, placenta, uterus, and testes. Additionally, expression is found in subendothelial vessel walls, pericytes, and fibroblasts that are not in direct contact with blood. About 1-2% of monocytes also express TF. TF is aberrantly expressed by various cancers, including cervical, non-small cell lung, endometrial, prostate, ovarian, esophageal, and bladder.

Factor VII and VIIa

1 Markham A. Drugs. 81(18):2141-2147. 2021.
2 Breij EC, de Goeij BE, Verploegen S, et al. Cancer Res. 74(4):1214-1226. 2014.
3 de Goeij BE, Satijn D, Freitag CM, et al. Mol Cancer Ther. 14(5):1130-1140. 2015.