Intracellular trafficking of new anticancer therapeutics: antibody-drug conjugates.
Ontology highlight
ABSTRACT:
SUBMITTER: Kalim M
PROVIDER: S-EPMC5546728 | biostudies-other | 2017
REPOSITORIES: biostudies-other
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Project description:Antibodies armed with biologic drugs could greatly expand the therapeutic potential of antibody-drug conjugates for cancer therapy, broadening their application to disease targets currently limited by intracellular delivery barriers. Additional selectivity and new therapeutic approaches could be realized with intracellular protein drugs that more specifically target dysregulated pathways in hematologic cancers and other malignancies. A multifunctional polymeric delivery system for enhanced cytosolic delivery of protein drugs has been developed that incorporates endosomal-releasing activity, antibody targeting, and a biocompatible long-chain ethylene glycol component for optimized safety, pharmacokinetics, and tumor biodistribution. The pH-responsive polymeric micelle carrier, with an internalizing anti-CD22 monoclonal targeting antibody, effectively delivered a proapoptotic Bcl-2 interacting mediator (BIM) peptide drug that suppressed tumor growth for the duration of treatment and prolonged survival in a xenograft mouse model of human B-cell lymphoma. Antitumor drug activity was correlated with a mechanistic induction of the Bcl-2 pathway biomarker cleaved caspase-3 and a marked decrease in the Ki-67 proliferation biomarker. Broadening the intracellular target space by more effective delivery of protein/peptide drugs could expand the repertoire of antibody-drug conjugates to currently undruggable disease-specific targets and permit tailored drug strategies to stratified subpopulations and personalized medicines.
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Project description:Progress in the treatment of cancer over the past decade has been slow. Targeting a mutated gene of an individual patient tumor, tumor-guided agents, and the first draft of the human genome sequence have created an overenthusiasm to achieve personalized medicine. However, we now know that this effort is misleading. Extreme interpatient and intratumor heterogeneity, scarce knowledge in how genome-wide mutational landscape and epigenetic changes affect transcriptional processes, gene expression, signaling transduction networks and cell regulation, and clinical assessment of temporary efficacy of targeted drugs explain the limitations of these currently available agents. Trastuzumab and a few other monoclonal antibodies or small-molecule tyrosine kinase inhibitors (TKIs) represent an exception to this rule. By blocking ligand-binding receptor in patients with human epidermal growth factor receptor 2 (HER2) amplification and overexpression, trastuzumab added to chemotherapy in HER2-positive patients has been proven to provide significant overall survival benefit in both metastatic and adjuvant settings. Lapatinib, a small-molecule dual inhibitor (TKI) of both HER2 and EGFR (epidermal growth factor receptor) pathways, has an antitumor activity translated into progression-free survival benefit in HER2-positive metastatic patients previously treated with a taxane, an anthracycline, and trastuzumab. Despite these advances, ~25% of patients with HER2-positive breast cancer experience recurrence in the adjuvant setting, while in the metastatic setting, median survival time is 25 months. In this review, we discuss the safety, efficacy, and limitations of the trastuzumab emtansine (T-DM1) conjugate in the treatment of HER2-positive metastatic breast cancer. We also highlight Phase III randomized trials, currently underway, using either the T-DM1 conjugate or various combinations of monoclonal antibodies and TKIs. Moreover, in contrast with all these agents developed on the basis of "central dogma" of simplified reductionist transcription and single gene-phenotype linear relationship, we summarize the emerging, amazing era of next-generation, transcriptional circuitry and intracellular signaling network-based drugs guided by the latest advances in genome science and dynamics of network biology.
| S-EPMC3969339 | biostudies-other
Project description:Synthetic derivatives of the microtubule-targeted agent maytansine, commonly known as drug maytansinoids or DMs, are emerging as potential cancer therapeutics. DM1 is an antibody-conjugatable maytansinoid that was developed to overcome systemic toxicity associated with maytansine and to enhance tumor-specific delivery. Antibody-DM1 conjugates showed promising results in preclinical and clinical evaluations. However, the molecular mechanism of the drug component DM1 was largely unknown. Recently, researchers have examined the mechanism of DM1 at molecular and cellular levels. According to their findings, DM1 binds at the tips of microtubules and suppresses the dynamicity of microtubules. The antibody-DM1 conjugate cleaves inside cells and releases the active drug in a time-dependent manner. The suppression of microtubule dynamics by DM1 induces mitotic arrest and cell death.
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Project description:BackgroundOsteosarcoma (OS), the most common bone tumor in children and adolescents, has high rates of metastasis leading to poor survival. Leucine-rich repeat containing 15 (LRRC15), a transmembrane protein whose expression is modulated by TGFβ, was recently shown to be highly expressed on the surface of OS tumor cells. Here, we evaluate a novel antibody-drug conjugate (ADC) targeting LRRC15 in OS human cell lines and murine xenografts. We compare this new ADC, which is conjugated to the anthracycline derivative PNU-159682 (PNU), to a previously studied LRRC15 ADC that is conjugated to the tubulin inhibitor monomethyl auristatin E (MMAE), since anthracyclines are standard of care in OS.ProcedureWe evaluated LRRC15 expression in OS cells using Western blots and flow cytometry, and analyzed the epigenetic landscape of the LRRC15 locus using chromatin immunoprecipitation. Efficacy of ADCs on cell growth was analyzed by IncuCyte live cell imaging. Intramuscular xenograft tumor growth was assessed by bioluminescence imaging and hematoxylin and eosin staining.ResultsLRRC15-PNU is more effective at inhibiting growth in vitro and in vivo than an isotype antibody control or the LRRC15-MMAE ADC in two high LRRC15 expressing OS cell lines. Low expressing cell lines are not sensitive to either ADC. Importantly, cells with low LRRC15 expression are amenable to re-expression after TGFβ treatment, suggesting a potential to sensitize insensitive OS cells to LRRC15 ADC treatment. In vivo, LRRC15-PNU had cure rates of 40-100% in OS xenograft models.ConclusionsOverall, LRRC15-directed ADCs are a promising new avenue for OS treatment.
| S-EPMC9137401 | biostudies-literature
Project description:Antibody-drug conjugates (ADCs) represent an attractive class of biopharmaceutical agents, with the potential to selectively deliver potent cytotoxic agents to tumors. It is generally assumed that ADC products should preferably bind and internalize into cancer cells in order to liberate their toxic payload, but a growing body of evidence indicates that also ADCs based on noninternalizing antibodies may be potently active. In this Communication, we investigated dipeptide-based linkers (frequently used for internalizing ADC products) in the context of the noninternalizing F16 antibody, specific to a splice isoform of tenascin-C. Using monomethyl auristatin E (MMAE) as potent cytotoxic drug, we observed that a single amino acid substitution of the Val-Cit dipeptide linker can substantially modulate the in vivo stability of the corresponding ADC products, as well as the anticancer activity in mice bearing the human epidermoid A431 carcinoma. In these settings, the linker based on the Val-Ala dipeptide exhibited better performances, compared to Val-Cit, Val-Lys, and Val-Arg analogues. Mass spectrometric analysis revealed that the four linkers displayed not only different stability in vivo but also differences in cleavage sites. Moreover, the absence of anticancer activity for a F16-MMAE conjugate featuring a noncleavable linker indicated that drug release modalities, based on proteolytic degradation of the immunoglobulin moiety, cannot be exploited with noninternalizing antibodies. ADC products based on the noninternalizing F16 antibody may be useful for the treatment of several human malignancies, as the cognate antigen is abundantly expressed in the extracellular matrix of several tumors, while being virtually undetectable in most normal adult tissues.
| S-EPMC5521252 | biostudies-literature
Project description:Limited clinical application of antibody-drug conjugates (ADCs) targeting tumor associated antigens (TAAs) is usually caused by on-target off-tumor side effect. Tumor-specific mutant antigens (TSMAs) only expressed in tumor cells which are ideal targets for ADCs. In addition, intracellular somatic mutant proteins can be presented on the cell surface by human leukocyte antigen class I (HLA I)molecules forming tumor-specific peptide/HLA I complexes. KRAS G12V mutation frequently occurred in varied cancer and was verified as a promising target for cancer therapy. In this study, we generated two TCR-mimic antibody-drug conjugates (TCRm-ADCs), 2E8-MMAE and 2A5-MMAE, targeting KRAS G12V/HLA-A*0201 complex, which mediated specific antitumor activity in vitro and in vivo without obvious toxicity. Our findings are the first time validate the strategy of TCRm-ADCs targeting intracellular TSMAs, which improves the safety of antibody-based drugs and provides novel strategy for precision medicine in cancer therapy.
| S-EPMC7750800 | biostudies-literature
Project description:Antibody-drug conjugates (ADCs) have provided new therapeutic options and significant promise for patients with cancer, particularly where existing treatments are limited. Substantial effort in ADC development is underway globally, with 13 ADCs currently approved and many more in development. The therapeutic benefits of ADCs leverage the ability to selectively target cancer cells through antibody binding, resultant relative sparing of non-malignant tissues, and the targeted delivery of a cytotoxic payload. Consequently, this drug class has demonstrated activity in multiple malignancies refractory to standard therapeutic options. Despite this, limitations exist, including narrow therapeutic windows, unique toxicity profiles, development of therapeutic resistance, and appropriate biomarker selection. This review will describe the development of ADCs, their mechanisms of action, pivotal trials, and approved indications and identify common themes. Current challenges and opportunities will be discussed for this drug class in cancer therapeutics at a time when significant developments in antibody therapies, immunotherapy, and targeted agents are occurring.
| S-EPMC10458257 | biostudies-literature
Project description:Antibody-drug conjugates (ADCs) are one of fastest growing classes of oncology drugs in modern drug development. By harnessing the powers of both cytotoxic chemotherapy and targeted therapy, ADCs are unique in offering the potential to deliver highly potent cytotoxic agents to cancer cells which express a pre-defined cell surface target. In lung cancer, the treatment paradigm has shifted dramatically in recent years, and now ADCs are now joining the list as potential options for lung cancer patients. Since 2020, the first ADC for NSCLC patients has been FDA-approved (trastuzumab deruxtecan) and two ADCs have been granted FDA Breakthrough Therapy Designation, currently under evaluation (patritumab deruxtecan, telisotuzumab vedotin). Furthermore, several early-phase trials are assessing various novel ADCs, either as monotherapy or in combinations with advanced lung cancer, and more selective and potent ADCs are expected to become therapeutic options in clinic soon. In this review, we discuss the structure and mechanism of action of ADCs, including insights from pre-clinical work; we summarize the ADCs' recent progress in lung cancer, describe toxicity profiles of ADCs, and explore strategies designed to enhance ADC potency and overcome resistance. In addition, we discuss novel ADC strategies of interest in lung cancer, including non-cytotoxic payloads, such as immunomodulatory and anti-apoptotic agents.
| S-EPMC9834242 | biostudies-literature
Project description:BackgroundAntibody-drug conjugates are attractive targeted agents in anticancer treatment because of their unique mechanism of action and reduced toxicity. Little is known about the spectrum of adverse events associated with antibody-drug conjugates, despite tens of clinical trials.MethodsA systematic review of randomized controlled trials evaluating antibody-drug conjugate efficacy in anticancer treatment was conducted. PubMed, EMBASE, and ClinicalTrial.gov were searched for relevant studies. Meta-analyses assessed the odds ratios (ORs) of 12 treatment-related symptoms and toxicities in patients treated with antibody-drug conjugates compared with those receiving other anticancer agents without antibody-drug conjugates. All-grade and high-grade (grade ≥3) toxicities were examined.ResultsTwenty studies involving 10 075 patients were included. Compared with control groups, antibody-drug conjugates were associated with a higher risk of all-grade fatigue (OR = 1.25, 95% confidence interval [CI] = 1.08 to 1.45), anorexia (OR = 1.36, 95% CI = 1.09 to 1.69), nausea (OR = 1.46, 95% CI = 1.09 to 1.97), and sensory neuropathy (OR = 2.18, 95% CI = 1.27 to 3.76) as treatment-related symptoms. Patients treated with antibody-drug conjugates had a statistically significantly lower risk of all-grade febrile neutropenia (OR = 0.46, 95% CI = 0.22 to 0.96). Conversely, they had a higher risk of thrombocytopenia (OR = 2.07, 95% CI = 1.00 to 4.31), increased alanine aminotransferase (OR = 2.51, 95% CI = 1.84 to 3.40), and increased aspartate aminotransferase (OR = 2.83, 95% CI = 2.04 to 3.93). Subgroup analysis showed a similar toxicity profile when comparing the solid tumors with hematologic malignancy groups and the antibody-drug conjugate vs antibody-drug conjugate plus chemotherapy groups, except for some neurologic and hematologic adverse events.ConclusionsThis comprehensive profile of adverse events associated with antibody-drug conjugate-based treatment shows an increase in various types of all-grade treatment-related symptoms and adverse events, although no increase in high-grade adverse events was seen.
| S-EPMC10579782 | biostudies-literature
Project description:Bioorthogonal catalysis provides a promising strategy for imaging and therapeutic applications, providing controlled in situ activation of pro-dyes and prodrugs. In this work, the use of a polymeric scaffold to encapsulate transition metal catalysts (TMCs), generating bioorthogonal "polyzymes," is presented. These polyzymes enhance the stability of TMCs, protecting the catalytic centers from deactivation in biological media. The therapeutic potential of these polyzymes is demonstrated by the transformation of a nontoxic prodrug to an anticancer drug (mitoxantrone), leading to the cancer cell death in vitro.
| S-EPMC7933084 | biostudies-literature