Efficient elimination of CD103-expressing cells by anti-CD103 antibody drug conjugates in immunocompetent mice

Mang, Yuanyi; Zhao, Zhihui; Zeng, Zhaolin; Wu, Xing; Li, Zhengjie; Zhang, Lei

doi:10.1016/j.intimp.2014.11.004

Cited by 5 publications

(11 citation statements)

References 38 publications

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“…Others have reported comparing cleavable versus noncleavable drug linkers, but typically, these comparisons have included the same warhead class; for example, comparing conjugates with either cleavable mc-VC-PABC-MMAE or noncleavable mc-MMAF (45,46), or cleavable SPDB-DM4 versus noncleavable SMCC-DM1 (47,48). There have also been reports of comparing conjugates with auristatins and maytansinoids (49), but these are both inherently two classes of drugs with a similar mechanism of action, namely microtubule inhibition.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Evaluation of MEDI0641, a Pyrrolobenzodiazepine-Conjugated Antibody–Drug Conjugate Targeting 5T4

Harper¹,

Lloyd²,

Dimasi³

et al. 2017

Molecular Cancer Therapeutics

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Antibody-drug conjugates (ADC) are used to selectively deliver cytotoxic agents to tumors and have the potential for increased clinical benefit to cancer patients. 5T4 is an oncofetal antigen overexpressed on the cell surface in many carcinomas on both bulk tumor cells as well as cancer stem cells (CSC), has very limited normal tissue expression, and can internalize when bound by an antibody. An anti-5T4 antibody was identified and optimized for efficient binding and internalization in a target-specific manner, and engineered cysteines were incorporated into the molecule for site-specific conjugation. ADCs targeting 5T4 were constructed by site-specifically conjugating the antibody with payloads that possess different mechanisms of action, either a DNA cross-linking pyrrolobenzodiazepine (PBD) dimer or a microtubule-destabilizing tubulysin, so that each ADC had a drug:antibody ratio of 2. The resulting ADCs demonstrated significant target-dependent activity in vitro and in vivo; however, the ADC conjugated with a PBD payload (5T4-PBD) elicited more durable antitumor responses in vivo than the tubulysin conjugate in xenograft models. Likewise, the 5T4-PBD more potently inhibited the growth of 5T4-positive CSCs in vivo, which likely contributed to its superior antitumor activity. Given that the 5T4-PBD possessed both potent antitumor activity as well as anti-CSC activity, and thus could potentially target bulk tumor cells and CSCs in target-positive indications, it was further evaluated in non-GLP rat toxicology studies that demonstrated excellent in vivo stability with an acceptable safety profile. Taken together, these preclinical data support further development of 5T4-PBD, also known as MEDI0641, against 5T4 þ cancer indications. Mol Cancer Ther;16(8); 1576-87. Ó2017 AACR.

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Section: Discussionmentioning

confidence: 99%

Preclinical Evaluation of MEDI0641, a Pyrrolobenzodiazepine-Conjugated Antibody–Drug Conjugate Targeting 5T4

Harper¹,

Lloyd²,

Dimasi³

et al. 2017

Molecular Cancer Therapeutics

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“…In addition, the VA-based linker also been mentioned in patents for a novel internalizing ADC that connected MMAE to antibody via a dibromo-containing linker, with any relevant druggable properties were provided [ 24 , 25 ]. The effect of different cytotoxin on the ADC is very significant, in addition to PBD and MMAE being two completely different molecules with different drug release process ( Figure 1 ) [ 14 , 26 ]. The VA peptide has an advantage in the preparation process and cost of materials, and may have the potential to improve ADC stability and decrease product aggregation [ 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Development and Properties of Valine-Alanine based Antibody-Drug Conjugates with Monomethyl Auristatin E as the Potent Payload

Wang

Fan²,

Zhong³

et al. 2017

IJMS

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Antibody-drug conjugates (ADCs), designed to selectively deliver cytotoxic agents to antigen-bearing cells, are poised to become an important class of cancer therapeutics. Human epithelial growth factor receptor (HER2) is considered an effective target for cancer treatment, and a HER2-targeting ADC has shown promising results. Most ADCs undergoing clinical evaluation contain linkers that have a lysosomal protease-cleavable dipeptide, of which the most common is valine-citrulline (VC). However, valine-alanine (VA), another dipeptide comprising two human essential amino acids, has been used in next generation ADCs loading new toxins, but the druggable properties of ADCs loaded the most popular monomethyl auristatin E (MMAE) remain to be further explored. In this study, we generated VA-based ADCs that connected MMAE to an anti-HER2 antibody. We studied the differences in the preparation process, in vitro stability, cathepsin B activity and in vitro cytotoxicity of VA-based ADC compared to the ADC of VC. VA had comparable performance to VC, which preliminarily displays its practicability. Additional efficacy and safety studies in a xenograft model indicate this novel ADC exerted potent anti-tumor activity and negligible toxicity. The results of this study show the application potential of VA-based ADC with MMAE as the payload.

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“…However, such nondepleting anti-CD103 mAbs fail to prolong the survival of tissue allografts. Hence, an anti-CD103 mAb (M290) was conjugated to various cytotoxins to achieve efficient depletion of CD103-expressing cells in vivo 10,11 . For example, M290-saporin (M290-SAP) has been demonstrated to deplete CD103-expressing leukocytes and promote indefinite survival of pancreatic islet allografts in MHC-mismatched mice 10,12 .…”

Section: Introductionmentioning

confidence: 99%

“…For example, M290-saporin (M290-SAP) has been demonstrated to deplete CD103-expressing leukocytes and promote indefinite survival of pancreatic islet allografts in MHC-mismatched mice 10,12 . Unfortunately, studies have shown that M290-SAP also depletes non-CD103-expressing T cells and causes significant weight loss 11 . As such, systemic toxicity restricts its clinical application.…”

Section: Introductionmentioning

confidence: 99%

“…As such, systemic toxicity restricts its clinical application. Our group previously synthesized three M290 antibody-drug conjugates (M290-ADCs) that efficiently and specifically depleted CD103-expressing cells in vivo without systemic toxicity 11 . In the present study, to evaluate the potential of the M290-ADCs in the therapeutic intervention of organ allograft rejection, one of the previously reported M290-ADCs (M290-MC-MMAF) was administered to streptozotocin (STZ)-induced diabetic mice with islet allograft transplantation.…”

Section: Introductionmentioning

confidence: 99%

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An anti-CD103 antibody-drug conjugate prolongs the survival of pancreatic islet allografts in mice

et al. 2019

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CD103 mediates T-cell infiltration and organ allograft rejection, and depletion of CD103-expressing cells is a promising therapeutic strategy for allograft intolerance. Recently, we verified that M290-MC-MMAF, an anti-CD103 antibody-drug conjugate, potently eliminates CD103-positive cells in vivo, with high specificity and minimal toxicity. However, the contribution of M290-MC-MMAF to blocking the CD103/E-cadherin pathway involved in transplant rejection remains unclear. Herein, we examined the impact of systemic administration of M290-MC-MMAF on allografts in an islet transplantation model. M290-MC-MMAF treatment maintained the long-term survival of islet allografts (>60 days) compared to mock injection or unconjugated M290 antibody treatment (<18 days). The change was associated with a decrease in CD103+CD8+ effector T cells and an increase in CD4+CD25+ regulatory T cells. CD103+CD8+ effector T-cell transfer or CD4+CD25+ regulatory T-cell depletion resulted in a rapid loss of allografts in long-surviving islet hosts. Moreover, M290-MC-MMAF treatment reduced IL-4, IL-6, and TNF-α expression levels and increased IL-10 expression in the grafts, which presented an immunosuppressive cytokine profile. In conclusion, targeting CD103 with M290-MC-MMAF induced immunosuppression and prolonged the survival of pancreatic islet allografts in mice, indicating the potential clinical value of M290-MC-MMAF in therapeutic interventions for allograft rejection.

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Efficient elimination of CD103-expressing cells by anti-CD103 antibody drug conjugates in immunocompetent mice

Cited by 5 publications

References 38 publications

Preclinical Evaluation of MEDI0641, a Pyrrolobenzodiazepine-Conjugated Antibody–Drug Conjugate Targeting 5T4

Preclinical Evaluation of MEDI0641, a Pyrrolobenzodiazepine-Conjugated Antibody–Drug Conjugate Targeting 5T4

Development and Properties of Valine-Alanine based Antibody-Drug Conjugates with Monomethyl Auristatin E as the Potent Payload

An anti-CD103 antibody-drug conjugate prolongs the survival of pancreatic islet allografts in mice

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