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Pharmaceutics Apr 2021HER-3 is becoming an attractive target for antibody-drug conjugate (ADC)-based therapy. Indeed, this receptor and its ligands are found to be overexpressed in several...
HER-3 is becoming an attractive target for antibody-drug conjugate (ADC)-based therapy. Indeed, this receptor and its ligands are found to be overexpressed in several malignancies, and re-activation of its downstream signaling axis is known to play a critical role in modulating the sensitivity of targeted therapeutics in different tumors. In this study, we generated a novel ADC named EV20/NMS-P945 by coupling the anti-HER-3 antibody EV20 with a duocarmycin-like derivative, the thienoindole (TEI) NMS-P528, a DNA minor groove alkylating agent through a peptidic cleavable linker. This ADC showed target-dependent cytotoxic activity in vitro on several tumor cell lines and therapeutic activity in mouse xenograft tumor models, including those originating from pancreatic, prostatic, head and neck, gastric and ovarian cancer cells and melanoma. Pharmacokinetics and toxicological studies in monkeys demonstrated that this ADC possesses a favorable terminal half-life and stability and it is well tolerated. These data support further EV20/NMS-P945 clinical development as a therapeutic agent against HER-3-expressing malignancies.
PubMed: 33918158
DOI: 10.3390/pharmaceutics13040483 -
Biomedicines Mar 2021Despite significant advances in treatment strategies over the past decade, selective treatment of breast cancer with limited side-effects still remains a great... (Review)
Review
Despite significant advances in treatment strategies over the past decade, selective treatment of breast cancer with limited side-effects still remains a great challenge. The cytochrome P450 (CYP) family of enzymes contribute to cancer cell proliferation, cell signaling and drug metabolism with implications for treatment outcomes. A clearer understanding of CYP expression is important in the pathogenesis of breast cancer as several isoforms play critical roles in metabolising steroid hormones and xenobiotics that contribute to the genesis of breast cancer. The purpose of this review is to provide an update on how the presence of CYPs impacts on standard of care (SoC) drugs used to treat breast cancer as well as discuss opportunities to exploit CYP expression for therapeutic intervention. Finally, we provide our thoughts on future work in CYP research with the aim of supporting ongoing efforts to develop drugs with improved therapeutic index for patient benefit.
PubMed: 33809117
DOI: 10.3390/biomedicines9030290 -
Drug Discovery Today Feb 2021The duocarmycins belong to a class of agent that has fascinated scientists for over four decades. Their exquisite potency, unique mechanism of action, and efficacy in... (Review)
Review
The duocarmycins belong to a class of agent that has fascinated scientists for over four decades. Their exquisite potency, unique mechanism of action, and efficacy in multidrug-resistant tumour models makes them attractive to medicinal chemists and drug hunters. However, despite great advances in fine-tuning biological activity through structure-activity relationship studies (SARS), no duocarmycin-based therapeutic has reached clinical approval. In this review, we provide an overview of the most promising strategies currently used and include both tumour-targeted prodrug approaches and antibody-directed technologies.
Topics: Animals; Antibodies; Antineoplastic Agents, Alkylating; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Duocarmycins; Humans; Neoplasms; Prodrugs; Structure-Activity Relationship
PubMed: 33232841
DOI: 10.1016/j.drudis.2020.11.020 -
Molecular Cancer Therapeutics Nov 2020B7-H3, also referred to as CD276, is a member of the B7 family of immune regulatory proteins. B7-H3 is overexpressed on many solid cancers, including prostate cancer,...
B7-H3, also referred to as CD276, is a member of the B7 family of immune regulatory proteins. B7-H3 is overexpressed on many solid cancers, including prostate cancer, renal cell carcinoma, melanoma, squamous cell carcinoma of the head and neck, non-small cell lung cancer, and breast cancer. Overexpression of B7-H3 is associated with disease severity, risk of recurrence and reduced survival. In this article, we report the preclinical development of MGC018, an antibody-drug conjugate targeted against B7-H3. MGC018 is comprised of the cleavable linker-duocarmycin payload, valine-citrulline- duocarmycin hydroxybenzamide azaindole (vc--DUBA), conjugated to an anti-B7-H3 humanized IgG1/kappa mAb through reduced interchain disulfides, with an average drug-to-antibody ratio of approximately 2.7. MGC018 exhibited cytotoxicity toward B7-H3-positive human tumor cell lines, and exhibited bystander killing of target-negative tumor cells when cocultured with B7-H3-positive tumor cells. MGC018 displayed potent antitumor activity in preclinical tumor models of breast, ovarian, and lung cancer, as well as melanoma. In addition, antitumor activity was observed toward patient-derived xenograft models of breast, prostate, and head and neck cancer displaying heterogeneous expression of B7-H3. Importantly, MGC018 exhibited a favorable pharmacokinetic and safety profile in cynomolgus monkeys following repeat-dose administration. The antitumor activity observed preclinically with MGC018, together with the positive safety profile, provides evidence of a potentially favorable therapeutic index and supports the continued development of MGC018 for the treatment of solid cancers. GRAPHICAL ABSTRACT: http://mct.aacrjournals.org/content/molcanther/19/11/2235/F1.large.jpg.
Topics: Animals; B7 Antigens; Bystander Effect; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Monitoring; Gene Knockdown Techniques; Humans; Immune Checkpoint Inhibitors; Immunoconjugates; Mice; Neoplasms; Treatment Outcome; Xenograft Model Antitumor Assays
PubMed: 32967924
DOI: 10.1158/1535-7163.MCT-20-0116 -
MedChemComm Dec 2019In a proof-of-concept study, solid phase synthesis allowed the rapid generation of a small molecule drug conjugate in which the glutamate carboxypeptidase II (GCPII)...
In a proof-of-concept study, solid phase synthesis allowed the rapid generation of a small molecule drug conjugate in which the glutamate carboxypeptidase II (GCPII) targeting small molecule DUPA was conjugated to the alkylating subunit of the potent cytotoxin duocarmycin SA. The targeted SMDC contained a cathepsin B cleavable linker, which was shown to be active and selective against cathepsin B over-expressing and GCPII-expressing tumour cell lines.
PubMed: 32879717
DOI: 10.1039/c9md00279k -
A near-infrared light-mediated cleavable linker strategy using the heptamethine cyanine chromophore.Methods in Enzymology 2020Optical methods offer the potential to manipulate living biological systems with exceptional spatial and temporal control. Caging bioactive molecules with photocleavable...
Optical methods offer the potential to manipulate living biological systems with exceptional spatial and temporal control. Caging bioactive molecules with photocleavable functional groups is an important strategy that could be applied to a range of problems, including the targeted delivery of otherwise toxic therapeutics. However existing approaches that require UV or blue light are difficult to apply in organismal settings due to issues of tissue penetration and light toxicity. Photocaging groups built on the heptamethine cyanine scaffold enable the targeted delivery of bioactive molecules using near-IR light (up to 780nm) in live animal settings. Here we provide a detailed procedure demonstrating the utility of the heptamethine cyanine caging group to create a light-cleavable linker between an antibody, panitumumab, and a therapeutic small molecule in the duocarmycin class of natural products. Descriptions of the design and synthesis of the small molecule component, assembly of the antibody conjugate, in vitro analysis of uncaging, in vivo imaging, and impact on tumor progression are provided.
Topics: Animals; Carbocyanines; Infrared Rays
PubMed: 32713525
DOI: 10.1016/bs.mie.2020.04.043 -
Bioconjugate Chemistry Sep 2020Engineering cysteines at specific sites in antibodies to create well-defined ADCs for the treatment of cancer is a promising approach to increase the therapeutic index...
Engineering cysteines at specific sites in antibodies to create well-defined ADCs for the treatment of cancer is a promising approach to increase the therapeutic index and helps to streamline the manufacturing process. Here, we report the development of an screening procedure to select for optimal sites in an antibody to which a hydrophobic linker-drug can be conjugated. Sites were identified inside the cavity that is naturally present in the Fab part of the antibody. Conjugating a linker-drug to these sites demonstrated the ability of the antibody to shield the hydrophobic character of the linker-drug while resulting ADCs maintained their cytotoxic potency . Comparison of site-specific ADCs versus randomly conjugated ADCs in an xenograft model revealed improved efficacy and exposure. We also report a selective reducing agent that is able to reduce the engineered cysteines while leaving the interchain disulfides in the oxidized state. This enables us to manufacture site-specific ADCs without introducing impurities associated with the conventional reduction/oxidation procedure for site-specific conjugation.
Topics: Animals; Antibiotics, Antineoplastic; Cell Line, Tumor; Cysteine; Duocarmycins; Humans; Hydrophobic and Hydrophilic Interactions; Immunoconjugates; Immunoglobulin G; Mice; Models, Molecular; Neoplasms; Oxidation-Reduction
PubMed: 32697078
DOI: 10.1021/acs.bioconjchem.0c00337 -
Bioconjugate Chemistry Jul 2020Solid-phase synthesis allowed the rapid generation of a peptide-drug conjugate. A peptide targeting the Thomsen-Friedenreich antigen (TFα) was conjugated to the...
Solid-phase synthesis allowed the rapid generation of a peptide-drug conjugate. A peptide targeting the Thomsen-Friedenreich antigen (TFα) was conjugated to the alkylating subunit of the potent cytotoxin duocarmycin SA. The compound, containing a cathepsin B cleavable linker, was shown to be active and selective against TFα expressing tumor cell lines.
Topics: Amino Acid Sequence; Antigens, Tumor-Associated, Carbohydrate; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Duocarmycins; Humans; Peptides
PubMed: 32515945
DOI: 10.1021/acs.bioconjchem.0c00282 -
Aging Cell Apr 2020Senescence is a stable growth arrest that impairs the replication of damaged, old or preneoplastic cells, therefore contributing to tissue homeostasis. Senescent cells...
Senescence is a stable growth arrest that impairs the replication of damaged, old or preneoplastic cells, therefore contributing to tissue homeostasis. Senescent cells accumulate during ageing and are associated with cancer, fibrosis and many age-related pathologies. Recent evidence suggests that the selective elimination of senescent cells can be effective on the treatment of many of these senescence-associated diseases. A universal characteristic of senescent cells is that they display elevated activity of the lysosomal β-galactosidase, and this has been exploited as a marker for senescence (senescence-associated β-galactosidase activity). Consequently, we hypothesized that galactose-modified cytotoxic prodrugs will be preferentially processed by senescent cells, resulting in their selective killing. Here, we show that different galactose-modified duocarmycin (GMD) derivatives preferentially kill senescent cells. GMD prodrugs induce selective apoptosis of senescent cells in a lysosomal β-galactosidase (GLB1)-dependent manner. GMD prodrugs can eliminate a broad range of senescent cells in culture, and treatment with a GMD prodrug enhances the elimination of bystander senescent cells that accumulate upon whole-body irradiation treatment of mice. Moreover, taking advantage of a mouse model of adamantinomatous craniopharyngioma (ACP), we show that treatment with a GMD prodrug selectively reduced the number of β-catenin-positive preneoplastic senescent cells. In summary, the above results make a case for testing the potential of galactose-modified duocarmycin prodrugs to treat senescence-related pathologies.
Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Cell Line; Cellular Senescence; Coculture Techniques; Craniopharyngioma; Duocarmycins; Galactose; Humans; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Prodrugs; beta-Galactosidase
PubMed: 32175667
DOI: 10.1111/acel.13133 -
Journal For Immunotherapy of Cancer Sep 2019Antibody-drug conjugates (ADCs) targeting the RON receptor, a tumorigenic factor contributing to cancer malignancy, has been considered as a novel strategy for cancer...
BACKGROUND
Antibody-drug conjugates (ADCs) targeting the RON receptor, a tumorigenic factor contributing to cancer malignancy, has been considered as a novel strategy for cancer therapy. Here we describe a humanized antibody recognizing the RON plexin-semaphorin-integrin (PSI) domain with increased drug delivery capability for potential clinical application.
METHOD
Monoclonal antibody PCM5B14 specific to the human and monkey RON PSI domain was generated and characterized by various immunological methods. Humanized antibody H5B14 was created by grafting PCM5B14 complementarity-determining regions into human IgG1/κ acceptor frameworks and conjugated with monomethyl auristatin E and duocarmycin to form two H5B14-based ADCs. Stability of H5B14-based ADCs in human plasma was measured using hydrophobic interaction chromatography. Various biochemical and biological assays were used to determine ADC- regulated RON internalization, cell viability, spheroid formation, and death of cancer stem-like cells. Efficacies of H5B14-based ADCs in vivo were validated using tumor xenograft models. Maximal tolerated doses of H5B14-based ADCs were established in mice.
RESULTS
H5B14 was highly specific to the human RON PSI domain and superior over other anti-RON ADCs in induction of RON internalization in various cancer cell lines tested. H5B14-based ADCS had a drug to antibody ratio of ~ 3.70:1 and were stable in human plasma with a minimal dissociation within a 10-day period. Functionally, H5B14-mediated drug delivery decreased cell viability at early stages with an average IC at ~ 20 nM in multiple cancer cell lines examined. H5B14-based ADCs also inhibited spheroid formation and caused death of cancer stem-like cells with RON/CD44/ESA phenotypes. In vivo, H5B14-based ADCs in a single injection inhibited tumor xenograft growth mediated by multiple cancer cell lines. Tumoristatic concentrations calculated from xenograft tumor models were in the range of 0.63 to 2.0 mg/kg bodyweight. Significantly, H5B14-based ADCs were capable of eradicating tumors at variable levels across multiple xenograft models regardless their malignant statuses. Toxicologically, H5B14-based ADCs were well tolerated in mice up to 60 mg/kg.
CONCLUSION
H5B14-based ADCs targeting the RON PSI domain are superior in inducing RON internalization, leading to robust drug delivery and overall inhibition and eradication of tumors in multiple xenograft models. These findings warrant H5B14-based ADCs for clinical trials in the future.
Topics: Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Duocarmycins; Female; Humans; Immunoconjugates; Maximum Tolerated Dose; Mice; Neoplasms; Oligopeptides; Protein Domains; Receptor Protein-Tyrosine Kinases; Xenograft Model Antitumor Assays
PubMed: 31519211
DOI: 10.1186/s40425-019-0732-8