An Antibody–Drug Conjugate That Targets Tissue Factor Exhibits Potent Therapeutic Activity against a Broad Range of Solid Tumors

Breij, Esther C.W.; Goeij, Bart E.C.G. de; Verploegen, Sandra; Schuurhuis, Danita H.; Amirkhosravi, Ali; Francis, John L.; Miller, Vibeke Breinholt; Houtkamp, Mischa; Bleeker, Wim K.; Satijn, David; Parren, Paul W.H.I.

doi:10.1158/0008-5472.can-13-2440

Cited by 167 publications

(181 citation statements)

References 37 publications

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“…Consistent with our observations, de Goeij and colleagues have recently demonstrated that high turnover of cytokine receptor type 2, Tissue Factor, enabled efficient intracellular delivery of ADC (44). Tissue Factor ADC effectively killed a tumor cell lines expressing as low as 2 Â 10 4 target molecules per cell (45). Taken together, our work and published data on Tissue Factor (44,45) indicate that high turnover proteins selectively expressed in tumors, but not in normal vital cells, may represent attractive ADC targets.…”

Section: Discussionsupporting

confidence: 90%

Bispecific Antibodies and Antibody–Drug Conjugates (ADCs) Bridging HER2 and Prolactin Receptor Improve Efficacy of HER2 ADCs

Andreev

Thambi

Bay

et al. 2017

Molecular Cancer Therapeutics

122

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The properties of cell surface proteins targeted by antibodydrug conjugates (ADCs) have not been fully exploited; of particular importance are the rate of internalization and the route of intracellular trafficking. In this study, we compared the trafficking of HER2, which is the target of the clinically approved ADC ado-trastuzumab emtansine (T-DM1), with that of prolactin receptor (PRLR), another potential target in breast cancer. In contrast to HER2, we found that PRLR is rapidly and constitutively internalized, and traffics efficiently to lysosomes, where it is degraded. The PRLR cytoplasmic domain is necessary to promote rapid internalization and degradation, and when transferred to HER2, enhances HER2 degradation. In accordance with these findings, low levels of cell surface PRLR ($30,000 surface receptors per cell) are sufficient to mediate effective killing by PRLR ADC, whereas cell killing by HER2 ADC requires higher levels of cell surface HER2 ($10 6 surface receptors per cell). Noncovalently crosslinking HER2 to PRLR at the cell surface, using a bispecific antibody that binds to both receptors, dramatically enhances the degradation of HER2 as well as the cell killing activity of a noncompeting HER2 ADC. Furthermore, in breast cancer cells that coexpress HER2 and PRLR, a HER2xPRLR bispecific ADC kills more effectively than HER2 ADC. These results emphasize that intracellular trafficking of ADC targets is a key property for their activity and, further, that coupling an ADC target to a rapidly internalizing protein may be a useful approach to enhance internalization and cell killing activity of ADCs.

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Section: Discussionsupporting

confidence: 90%

Bispecific Antibodies and Antibody–Drug Conjugates (ADCs) Bridging HER2 and Prolactin Receptor Improve Efficacy of HER2 ADCs

Andreev

Thambi

Bay

et al. 2017

Molecular Cancer Therapeutics

122

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“…4B, D, and F, where duostatin-3-conjugated antibodies did not induce bystander kill. Whereas TF-011-MMAE induced potent bystander kill which was in line with results published previously (4,33). To study the target requirements needed for efficient intracellular drug delivery, a drug-linker that only affects antigen-expressing cells was preferred.…”

Section: In Vitro Cytotoxicity Induced By Duostatin-3-conjugated Tf supporting

confidence: 81%

“…TF-011-MMAE showed potent antitumor activity in xenograft models derived from a broad range of solid cancers, and an acceptable safety profile in nonclinical toxicity studies (4). TF-011-MMAE and unconjugated TF-011 induced efficient antibody-dependent cell-mediated cytotoxicity and inhibition of TF:FVIIa-dependent intracellular signaling, both of which may contribute to the antitumor activity of TF-011-MMAE.…”

Section: Introductionmentioning

confidence: 95%

“…TF antibodies were previously described (4). In brief, TF-011 binds TF, interferes with FVIIa binding, and inhibits ERK phosphorylation.…”

Section: Antibody Generation and Conjugationmentioning

confidence: 99%

“…This includes the development of HuMax-TF-ADC (TF-011-MMAE), a novel ADC designed to deliver the cytotoxic payload MMAE to tumor cells expressing tissue factor (TF; ref. 4).…”

Section: Introductionmentioning

confidence: 99%

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High Turnover of Tissue Factor Enables Efficient Intracellular Delivery of Antibody–Drug Conjugates

Goeij

Satijn

Freitag

et al. 2015

Molecular Cancer Therapeutics

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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 TFspecific 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.

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Overview of ADME and PK/PD of ADCs

Zhao

Han

2015

Pharmaceutical Sciences Encyclopedia

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This chapter primarily discusses the absorption, distribution, metabolism/catabolism, and elimination (ADME) properties for antibody‐drug conjugates (ADCs) in oncology therapy and associated pharmacokinetic (PK) and pharmacokinetic/pharmacodynamics (PK/PD) modeling of ADCs. Drug‐linker stability is a key attribute required for the development of a successful ADC and has been a primary focus in ADC technology. Premature release of the conjugated drug prior to reaching its intended target may cause unwanted systemic toxicity and reduce the amount of drug delivered to the target tissues. An exposure‐response relationship exists for all therapeutic proteins and small molecule drugs. Multiple modeling efforts have been attempted to incorporate the deconjugation process and/or nonlinear clearance in ADC PK models. A full mechanistic PK model encompassing all major processes of ADC distribution, binding, and elimination of different drug‐to‐antibody ratio (DAR) species was proposed and multiple approximations were applied to simplify the model based on different assumptions.

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An Antibody–Drug Conjugate That Targets Tissue Factor Exhibits Potent Therapeutic Activity against a Broad Range of Solid Tumors

Abstract: Tissue factor (TF)

Cited by 167 publications

References 37 publications

Bispecific Antibodies and Antibody–Drug Conjugates (ADCs) Bridging HER2 and Prolactin Receptor Improve Efficacy of HER2 ADCs

Bispecific Antibodies and Antibody–Drug Conjugates (ADCs) Bridging HER2 and Prolactin Receptor Improve Efficacy of HER2 ADCs

High Turnover of Tissue Factor Enables Efficient Intracellular Delivery of Antibody–Drug Conjugates

Overview of ADME and PK/PD of ADCs

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