Molecular imaging reveals biodistribution of P-cadherin LP-DART bispecific and trafficking of adoptively transferred T cells in mouse xenograft model

Gupta, Vijay; Root, Adam; Fisher, Timothy S.; Norberg, Rand; David, John; Clark, Tracey; Cohen, Justin D.; May, Chad; Giddabasappa, Anand

doi:10.18632/oncotarget.27544

Cited by 6 publications

(7 citation statements)

References 34 publications

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“…These findings suggest that a certain number of pre-existing T cells in the tumor is essential for initial inflammation and subsequent peripheral T cell recruitment. Supporting this idea, we performed simultaneous in vivo imaging of a T-BsAb and T cells as in the aforementioned system [66] and confirmed that peak T cell accumulation occurred after the T-BsAb was delivered to the tumor (data not shown). Our results revealed that the T-BsAb first contacted the tumor cells and then brought in peripheral T cells.…”

Section: Redirection Of Antitumor Immunitymentioning

confidence: 59%

“…The authors labeled isolated T cells and their T-BsAb with two separate dyes that fluoresced at different wavelengths in order to distinguish between antibodies and T cells. They observed co-localization of their T-BsAb and T cells in tumors, and fluorescent signals from T cells peaked at 192 h after T-BsAb administration [66]. While these reports indicated an increased T cell quantity within tumors using in vivo imaging systems, several mechanistic studies have been performed to elucidate the cellular and molecular mechanism of the events involved.…”

Section: Redirection Of Antitumor Immunitymentioning

confidence: 99%

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T Cell Bispecific Antibodies: An Antibody-Based Delivery System for Inducing Antitumor Immunity

2021

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As a breakthrough immunotherapy, T cell bispecific antibodies (T-BsAbs) are a promising antibody therapy for various kinds of cancer. In general, T-BsAbs have dual-binding specificity to a tumor-associated antigen and a CD3 subunit forming a complex with the TCR. This enables T-BsAbs to crosslink tumor cells and T cells, inducing T cell activation and subsequent tumor cell death. Unlike immune checkpoint inhibitors, which release the brake of the immune system, T-BsAbs serve as an accelerator of T cells by stimulating their immune response via CD3 engagement. Therefore, they can actively redirect host immunity toward tumors, including T cell recruitment from the periphery to the tumor site and immunological synapse formation between tumor cells and T cells. Although the low immunogenicity of solid tumors increases the challenge of cancer immunotherapy, T-BsAbs capable of immune redirection can greatly benefit patients with such tumors. To investigate the detailed relationship between T-BsAbs delivery and their T cell redirection activity, it is necessary to determine how T-BsAbs deliver antitumor immunity to the tumor site and bring about tumor cell death. This review article discusses T-BsAb properties, specifically their pharmacokinetics, redirection of anticancer immunity, and local mechanism of action within tumor tissues, and discuss further challenges to expediting T-BsAb development.

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Section: Redirection Of Antitumor Immunitymentioning

confidence: 59%

Section: Redirection Of Antitumor Immunitymentioning

confidence: 99%

T Cell Bispecific Antibodies: An Antibody-Based Delivery System for Inducing Antitumor Immunity

2021

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“…We have previously shown that FMT imaging aids understanding of the three pillars of drug development: targeting/distribution, binding to the target, and the expression of pharmacology. 30 , 31 In this study, we again used FMT to demonstrate that the anti-IL13Rα2 Ab was able to target IL13Rα2-expressing tumors, exhibited favorable PK characteristics that are consistent with full-length antibodies, and that anti-IL13Rα2-ADC with an auristatin payload exhibited in vitro and in vivo anti-tumor activity. Since FMT is restricted to use in preclinical imaging, we also studied the biodistribution and tumor targeting of anti-IL13Rα2-Ab by PET imaging, a modality that is readily translatable to the clinic.…”

Section: Discussionmentioning

confidence: 90%

Targeting and pharmacology of an anti-IL13Rα2 antibody and antibody-drug conjugate in a melanoma xenograft model

Gupta

Jiang

Yang

et al. 2021

mAbs

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IL13Rα2 is a cell surface tumor antigen that is overexpressed in multiple tumor types. Here, we studied biodistribution and targeting potential of an anti-IL13Rα2 antibody (Ab) and anti-tumor activity of anti-IL13Rα2-antibody-drug conjugate (ADC). The anti-IL13Rα2 Ab was labeled with fluorophore AF680 or radioisotope 89 Zr for in vivo tracking using fluorescence molecular tomography (FMT) or positron emission tomography (PET) imaging, respectively. Both imaging modalities showed that the tumor was the major uptake site for anti-IL13Rα2-Ab, with peak uptake of 5–8% ID and 10% ID/g as quantified from FMT and PET, respectively. Pharmacological in vivo competition with excess of unlabeled anti-IL13Rα2-Ab significantly reduced the tumor uptake, indicative of antigen-specific tumor accumulation. Further, FMT imaging demonstrated similar biodistribution and pharmacokinetic profiles of an auristatin-conjugated anti-IL13Rα2-ADC as compared to the parental Ab. Finally, the anti-IL13Rα2-ADC exhibited a dose-dependent anti-tumor effect on A375 xenografts, with 90% complete responders at a dose of 3 mg/kg. Taken together, both FMT and PET showed a favorable biodistribution profile for anti-IL13Rα2-Ab/ADC, along with antigen-specific tumor targeting and excellent therapeutic efficacy in the A375 xenograft model. This work shows the great potential of this anti-IL13Rα2-ADC as a targeted anti-cancer agent.

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“…P-cadherin constitutes an attractive target with therapeutic potential to treat tumours that highly express this protein, with several studies addressing its target using different approaches [116][117][118][119]. In fact, for breast cancer, PCA062, a P-cadherin-targeting antibody-drug conjugate may have clinical potential, since it has been shown to have potent antitumour activity with acceptable efficacy and tolerability in preclinical studies in primates [120].…”

Section: Cadherin-3 (P-cadherin)mentioning

confidence: 99%

“…PF-06671008 is a CD3-bispecific molecule-targeting P-cadherin that was able to promote T-cell-mediated regression of established tumours in mice models. Importantly, PF-06671008 is already in phase I clinical trials (NCT02659631) for triple-negative breast cancer patients [118,121].…”

Section: Cadherin-3 (P-cadherin)mentioning

confidence: 99%

Breast Cancer Stem Cell Membrane Biomarkers: Therapy Targeting and Clinical Implications

Conde

Ribeiro

Paredes

2022

Cells

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Breast cancer is the most common malignancy affecting women worldwide. Importantly, there have been significant improvements in prevention, early diagnosis, and treatment options, which resulted in a significant decrease in breast cancer mortality rates. Nevertheless, the high rates of incidence combined with therapy resistance result in cancer relapse and metastasis, which still contributes to unacceptably high mortality of breast cancer patients. In this context, a small subpopulation of highly tumourigenic cancer cells within the tumour bulk, commonly designated as breast cancer stem cells (BCSCs), have been suggested as key elements in therapy resistance, which are responsible for breast cancer relapses and distant metastasis. Thus, improvements in BCSC-targeting therapies are crucial to tackling the metastatic progression and might allow therapy resistance to be overcome. However, the design of effective and specific BCSC-targeting therapies has been challenging since there is a lack of specific biomarkers for BCSCs, and the most common clinical approaches are designed for commonly altered BCSCs signalling pathways. Therefore, the search for a new class of BCSC biomarkers, such as the expression of membrane proteins with cancer stem cell potential, is an area of clinical relevance, once membrane proteins are accessible on the cell surface and easily recognized by specific antibodies. Here, we discuss the significance of BCSC membrane biomarkers as potential prognostic and therapeutic targets, reviewing the CSC-targeting therapies under clinical trials for breast cancer.

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Molecular imaging reveals biodistribution of P-cadherin LP-DART bispecific and trafficking of adoptively transferred T cells in mouse xenograft model

Cited by 6 publications

References 34 publications

T Cell Bispecific Antibodies: An Antibody-Based Delivery System for Inducing Antitumor Immunity

T Cell Bispecific Antibodies: An Antibody-Based Delivery System for Inducing Antitumor Immunity

Targeting and pharmacology of an anti-IL13Rα2 antibody and antibody-drug conjugate in a melanoma xenograft model

Breast Cancer Stem Cell Membrane Biomarkers: Therapy Targeting and Clinical Implications

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