Reinforcement of antitumor effect of micelles containing anticancer drugs by binding of an anti-tissue factor antibody without direct cytocidal effects

Tissue factor (TF), the trigger protein of the extrinsic blood coagulation cascade, is abundantly expressed in various cancers including gastric cancer. Anti‐TF monoclonal antibodies (mAbs) capable of targeting cancers have been successfully applied to armed antibodies such as antibody‐drug conjugates (ADCs) and molecular imaging probes. We prepared an anti‐TF mAb, clone 1084, labeled with astatine‐211 (211At), as a promising alpha emitter for cancer treatment. Alpha particles are characterized by high linear energy transfer and a range of 50‐100 µm in tissue. Therefore, selective and efficient tumor accumulation of alpha emitters results in potent antitumor activities against cancer cells with minor effects on normal cells adjacent to the tumor. Although the 211At‐conjugated clone 1084 (211At‐anti‐TF mAb) was disrupted by an 211At‐induced radiochemical reaction, we demonstrated that astatinated anti‐TF mAbs eluted in 0.6% or 1.2% sodium ascorbate (SA) solution were protected from antibody denaturation, which contributed to the maintenance of cellular binding activities and cytocidal effects of this immunoconjugate. Although body weight loss was observed in mice administered a 1.2% SA solution, the loss was transient and the radioprotectant seemed to be tolerable in vivo. In a high TF–expressing gastric cancer xenograft model, 211At‐anti‐TF mAb in 1.2% SA exerted a significantly greater antitumor effect than nonprotected 211At‐anti‐TF mAb. Moreover, the antitumor activities of the protected immunoconjugate in gastric cancer xenograft models were dependent on the level of TF in cancer cells. These findings suggest the clinical availability of the radioprotectant and applicability of clone 1084 to 211At‐radioimmunotherapy.

show abstract

“…According to a protocol described previously, we determined TF expression on gastric cancer cell lines using clone 1084 as a primary antibody 29 …”

Section: Methodsmentioning

confidence: 99%

“…TF is one of the attractive target molecules for cancer treatment with an armed antibody because various anti‐TF mAbs have been successfully applied to ADC 14‐21 and its antibody‐photosensitizer conjugate 22 . Thus, we produced anti‐TF mAbs for cancer targeting 16,19,22‐29 …”

Section: Introductionmentioning

confidence: 99%

Radioimmunotherapy with an ²¹¹At‐labeled anti–tissue factor antibody protected by sodium ascorbate

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Intensively investigated systems were based on copolymers containing blocks of poly(ethylene oxide) and poly(aspartic acid). Initially these copolymers were used as building blocks for making polymeric micelles with drugs conjugated to poly(aspartic acid) chains [ 134 , 135 , 136 , 137 ]. Positive results of phase 1 clinical study were already published for micelles with conjugated epirubicin [ 245 ].…”

Section: Preparation Of Functionalized Nano- and Microparticlesmentioning

confidence: 99%

“…Depending on block length, they self-assemble into polymeric micelles. In spite of the fact that the first paper on the aforementioned copolymers as drug carriers was published by Kataoka et al more than thirty years ago [132,133], studies in this field have been developing especially fast in the last few years [134][135][136][137].…”

Section: Biopolymersmentioning

confidence: 99%

Functionalized Particles Designed for Targeted Delivery

et al. 2021

View full text Add to dashboard Cite

Pure bioactive compounds alone can only be exceptionally administered in medical treatment. Usually, drugs are produced as various forms of active compounds and auxiliary substances, combinations assuring the desired healing functions. One of the important drug forms is represented by a combination of active substances and particle-shaped polymer in the nano- or micrometer size range. The review describes recent progress in this field balanced with basic information. After a brief introduction, the paper presents a concise overview of polymers used as components of nano- and microparticle drug carriers. Thereafter, progress in direct synthesis of polymer particles with functional groups is discussed. A section is devoted to formation of particles by self-assembly of homo- and copolymer-bearing functional groups. Special attention is focused on modification of the primary functional groups introduced during particle preparation, including introduction of ligands promoting anchorage of particles onto the chosen living cell types by interactions with specific receptors present in cell membranes. Particular attention is focused on progress in methods suitable for preparation of particles loaded with bioactive substances. The review ends with a brief discussion of the still not answered questions and unsolved problems.

show abstract

“…Thus, the laboratory responsible for its development has turned to another anti-TF clone, 1859, for further clinical development. Antibody 1859 conjugated to epirubicin-incorporating micelles selectively accumulates in TF-expressing tumors and suppresses tumor growth in mice [ 135 ]. In addition to MMAE conjugation, antibody 1084 has also been labelled with astatine-211, an α-emitting radioisotope; 211At-anti-TF mAb was shown to have anti-tumor activity commensurate with tumor TF-expression level in gastric cancer cell-line xenografts [ 137 ].…”

Section: Therapeutic Targeting Of Astfmentioning

confidence: 99%

Functional Characteristics and Regulated Expression of Alternatively Spliced Tissue Factor: An Update

Matiash

Lewis

Bogdanov

2021

Cancers

View full text Add to dashboard Cite

In human and mouse, alternative splicing of tissue factor’s primary transcript yields two mRNA species: one features all six TF exons and encodes full-length tissue factor (flTF), and the other lacks exon 5 and encodes alternatively spliced tissue factor (asTF). flTF, which is oftentimes referred to as “TF”, is an integral membrane glycoprotein due to the presence of an alpha-helical domain in its C-terminus, while asTF is soluble due to the frameshift resulting from the joining of exon 4 directly to exon 6. In this review, we focus on asTF—the more recently discovered isoform of TF that appears to significantly contribute to the pathobiology of several solid malignancies. There is currently a consensus in the field that asTF, while dispensable to normal hemostasis, can activate a subset of integrins on benign and malignant cells and promote outside-in signaling eliciting angiogenesis; cancer cell proliferation, migration, and invasion; and monocyte recruitment. We provide a general overview of the pioneering, as well as more recent, asTF research; discuss the current concepts of how asTF contributes to cancer progression; and open a conversation about the emerging utility of asTF as a biomarker and a therapeutic target.

show abstract

Reinforcement of antitumor effect of micelles containing anticancer drugs by binding of an anti-tissue factor antibody without direct cytocidal effects

Cited by 14 publications

References 33 publications

Radioimmunotherapy with an ²¹¹At‐labeled anti–tissue factor antibody protected by sodium ascorbate

Radioimmunotherapy with an ²¹¹At‐labeled anti–tissue factor antibody protected by sodium ascorbate

Functionalized Particles Designed for Targeted Delivery

Functional Characteristics and Regulated Expression of Alternatively Spliced Tissue Factor: An Update

Contact Info

Product

Resources

About

Reinforcement of antitumor effect of micelles containing anticancer drugs by binding of an anti-tissue factor antibody without direct cytocidal effects

Cited by 14 publications

References 33 publications

Radioimmunotherapy with an 211At‐labeled anti–tissue factor antibody protected by sodium ascorbate

Radioimmunotherapy with an 211At‐labeled anti–tissue factor antibody protected by sodium ascorbate

Functionalized Particles Designed for Targeted Delivery

Functional Characteristics and Regulated Expression of Alternatively Spliced Tissue Factor: An Update

Contact Info

Product

Resources

About

Radioimmunotherapy with an ²¹¹At‐labeled anti–tissue factor antibody protected by sodium ascorbate

Radioimmunotherapy with an ²¹¹At‐labeled anti–tissue factor antibody protected by sodium ascorbate