Search Results (61)

Cyanobacteria-derived peptides represent a promising class of anticancer agents due to their structural diversity and potent bioactivity. They exert cytotoxic effects through mechanisms including microtubule disruption, histone deacetylase inhibition, and apoptosis induction. Several peptides—most notably the dolastatin-derived auristatins—have achieved clinical success as cytotoxic payloads in antibody–drug conjugates (ADCs). However, challenges such as limited tumor selectivity, systemic toxicity, and production scalability remain barriers to broader application. Recent advances in targeted delivery technologies, combination therapy strategies, synthetic biology, and genome mining offer promising solutions. Emerging data from preclinical and clinical studies highlight their therapeutic potential, particularly in treatment-resistant cancers. In this review, we (i) summarize key cyanobacterial peptides and their molecular mechanisms of action, (ii) examine progress toward clinical translation, and (iii) explore biotechnological approaches enabling sustainable production and structural diversification. We also discuss future directions for enhancing specificity and the therapeutic index to fully exploit the potential of these marine-derived peptides in oncology. Full article

Prostate cancer is the most common tumor in men in developed countries and it often responds poorly to conventional treatments. Monoclonal antibody (MoAb) therapy, for this pathology, has grown tremendously in the past decades, exploiting naked and conjugated antibodies to cytotoxic payloads to form antibody drug conjugates (ADCs). Several studies have been carried out conjugating biomolecules against prostate-specific membrane antigen (PSMA), highly expressed in this tumor, to cytotoxic drugs. Nano-based formulations show high potential in targeted drug delivery to enhance the bioavailability of drugs. Our research aimed to evaluate the feasibility of setting up a nanoparticle-based multimodal tool for targeted drug delivery, describing the step-by-step approach and to perform a first screening of these fluorescent PEGylated silica nanoparticles employed in selective cancer cell targeting and killing. These nanoparticles featured a core–shell structure to contemporarily conjugate the antibody and the cytotoxic payload monomethyl auristatin E (MMAE) using a step-by-step approach. We compared the cytotoxic effect of this multimodal nanotool near the antibody-MMAE and free MMAE. We found a lower cytotoxicity effect of the nanoparticle-based construct compared to free drugs, likely because of the preservation of the previously observed receptor-mediated endocytosis. Nanomedicine is confirmed as a powerful alternative to organic drug delivery systems, even if some aspects, such as drug loading efficacy, release, scalable manufacturing and long-term stability, need to be deepened. Full article

Background/Objectives: The gene F3, encoding Tissue Factor (TF), is expressed in many cancers and contributes to their malignancy. Among adult-type diffuse gliomas, IDH1/2 wild-type (IDH^wt) glioblastomas (GBM) express more TF than IDH1/2 mutant (IDH^mut) gliomas. Tisotumab vedotin (TisVed), an anti-TF antibody conjugated to monomethyl auristatin E, is a therapeutic designed to target cells expressing TF. We therefore sought to determine the therapeutic potential of TisVed in IDH^wt vs. IDH^mut gliomas. Methods: We treated IDH^wt and IDH^mut patient-derived glioma cells with control IgG, unconjugated tisotumab (Tis), or TisVed in vitro, followed by cell viability assays and the assessment of TF signaling. We tested Tis and TisVed in mice intracranially engrafted with patient-derived IDH^wt and IDH^mut gliomas and mice flank engrafted with IDH^wt GBM. Results: TisVed was more active against cultured IDH^wt GBM cells than IDH^mut glioma cells. This activity was increased by the daily washout of soluble TF secreted by IDH^wt GBM cells. Unconjugated Tis had less effect than TisVed, and TF signaling was minimally inhibited. TisVed extended the survival of mice intracranially engrafted with IDH^wt GBM (p = 0.006), but not mice with IDH^mut glioma (p = 0.88). TisVed also reduced the growth of IDH^wt GBM flank xenografts. Tis alone had no antitumor effect in either setting. Notably, both TisVed and Tis were associated with hemorrhage in flank tumors. Conclusions: TisVed targets high-TF-expressing IDH^wt GBM, but not low-TF-expressing IDH^mut glioma. This is predominately through the vedotin conjugate rather than inhibition of TF signaling. Though the effect size is modest, TisVed shows anticancer effects against IDH^wt GBM. However, there could be complications related to hemostasis and hemorrhage. Full article

A human epidermal growth factor receptor 2 (HER2)-specific nanobody called 2Rs15d, containing a His3LysHis6 segment at the C-terminus, was recombinantly produced. Subsequent site-selective acylation on the C-terminally activated lysine residue allowed installation of the cytotoxin monomethyl auristatin E-functionalized cathepsin B-sensitive payload to provide a highly homogenous nanobody–drug conjugate (NBC), which demonstrated high potency and selectivity for HER2-positive breast cancer models. Full article

Background: Human immunodeficiency virus (HIV) establishes latent infections in cellular reservoirs, including microglia. HC69 cells, a microglial model of HIV latency, contain an HIV promoter long terminal repeat (LTR)-GFP reporter and were used for testing the efficacy of a two-step magnetoelectric nanoparticle (MENP) and extracellular vesicle (xEV) latency-targeting (MELT) nanotherapeutic. GFP expression in HC69 at rest is low (GFP^Lo), and upon exposure to LTR, transcription-activating agents (i.e., TNF-α) are induced to be high expressing (GFP^Hi). Methods: The first step of MELT utilized ZL0580, an HIV Tat inhibitor loaded into EVs (80%) via incubation. ZL0580-EVs were taken up by GFP^Lo and blocked LTR transcriptional reactivation by 50% and were 90% less toxic than ZL0580 alone. The second step in MELT involved conjugation of monomethyl auristatin E (MMAE) to MENPs. HPLC measurements showed 80% MMAE attachment to MENPs. Flow cytometry-based measurements of the membrane potential indicated that the membranes of GFP^Hi HC69 were 60% more polarized than GFP^Lo HC69 cells. More MMAE–MENPs were internalized by GFP^Lo HC69. Results: Using a mixed-cell blood–brain barrier (BBB) Transwell model, we demonstrated that 20% of MELT crossed the BBB, was taken up by HC69 cells, and reduced LTR reactivation by 10%. Conclusions: Overall, this study demonstrated that MELT can potentially be utilized as a nanotherapeutic to target HIV latency in microglia. Full article

Homogeneous antibody–drug conjugates (ADCs) exhibit significantly improved pharmacological properties compared to their heterogeneous counterparts. Site-specific conjugation of the payload to the IgG required for homogeneity can be achieved using enzymes. One example is microbial transglutaminase (MTGase), which can selectively perform transamidation on the Q295 residue of human Fc when N297 glycans are removed. As a result, two modifications can be introduced per IgG molecule; however, achieving higher drug-to-antibody ratios (DARs) requires the use of branched linkers. While several such linkers have been reported, little information is available on the relationship between linker structure and ADC properties. To address this gap, we synthesized two branched amino triazide linkers, differing by a PEG₄ fragment inserted after the branching point, which were used to prepare two homogeneous trastuzumab-based DAR 6 ADCs (a “short” and a “long” one). This was achieved by a two-step process consisting of enzymatic linker conjugation followed by bioorthogonal coupling with a cleavable linker bearing monomethyl auristatin E (MMAE). Two other trastuzumab–MMAE conjugates were used as controls: a heterogeneous DAR 6 ADC, made using conventional thiol–maleimide chemistry, and a homogeneous DAR 2 ADC. We found that, while the four conjugates had identical affinity for HER2, their cytotoxicity differed significantly: the “long” homogeneous DAR 6 ADC was just as active as its heterogeneous counterpart, but the “short” DAR 6 ADC was an order of magnitude less potent, inferior even to the DAR 2 conjugate. Our findings indicate that the length of the branched linker critically affects the cytotoxic activity of ADCs, possibly due to steric hindrance influencing the rate of linker cleavage by lysosomal enzymes. Full article

Chemotherapies remain standard therapy for cancers but have limited efficacy and cause significant side effects, highlighting the need for targeted approaches. In the progression of cancer, tumors increase matrix metalloproteinase (MMP) activity. Leveraging and therapeutically redirecting tumor MMPs through activatable cell-penetrating peptide (ACPP) technology offers new approaches for tumor-selective drug delivery and for studying how drug payloads engage the tumor immune microenvironment. ACPPs are biosensing peptides consisting of a drug-conjugated polycationic cell-penetrating peptide masked by an autoinhibitory polyanionic peptide through an interlinking peptide linker. Since tumors overexpress MMPs, ACPP tumor-targeting is achieved using an MMP cleavable linker. Monomethyl auristatin E (MMAE) is a potent anti-tubulin and common drug payload in antibody drug conjugates; however there are limited pre-clinical studies on how this clinically effective drug modulates the interplay of cancer cells and the immune system. Here, we report the versatility of ACPP conjugates in syngeneic murine cancer models and interrogate how MMAE temporally alters the tumor immune microenvironment. We show that cRGD-ACPP-MMAE preferentially delivered MMAE to tumors in murine models. Targeted cRGD-ACPP-MMAE demonstrated anti-tumor kill activity that activated the innate and adaptive arms of the immune system. Understanding how targeted MMAE engages tumors can optimize MMAE tumor kill activity and inform rational combinations with other cancer therapeutics. Full article

Background/Objectives: Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) that combines monomethyl auristatin E (MMAE), a potent cytotoxic agent, with a monoclonal antibody targeting Nectin-4. It has emerged as a promising therapy for metastatic urothelial carcinoma (mUC), either as monotherapy or in combination with pembrolizumab, improving significantly the overall survival of these patients. EV is associated with common adverse events, including skin reactions, glucose imbalance, and peripheral neuropathy, which are usually mild in severity and easily manageable. Methods: Following an initial case of pleuro-pneumopathy occurring in a patient treated with EV, we conducted a retrospective analysis of EV effects on pulmonary imaging. Results: In a cohort of 20 all-comers mUC patients, we identified three cases of potentially EV-related lung toxicity, resulting in a pleuro-pneumopathy rate of 15%. Two of these cases appeared highly symptomatic and required high steroid doses, with a rapid resolution of symptoms and normalization of radiological findings. In one patient, rechallenge of EV was associated with reoccurrence of pneumopathy. We described the clinical and radiological features of these cases, as well as their evolution after EV discontinuation and rechallenge. Conclusions: This case series underscores the importance of close pulmonary monitoring during EV treatment. Full article

Randomized phase III trial results have demonstrated enfortumab vedotin (EV), an antibody–drug conjugate (ADC) consisting of an anti-Nectin-4 human IgG1 monoclonal antibody and monomethyl auristatin E, is a useful treatment for patients with locally advanced or metastatic urothelial carcinoma (la/mUC) that progressed after immune checkpoint inhibitor (ICI) therapies. This multicenter retrospective cohort study aimed to identify predictive factors for the efficacy of EV therapy and prolonged overall survival (OS) of patients in clinical practice. This study included patients with la/mUC who received ICI treatment. Patients who subsequently received EV treatment, those who received non-EV chemotherapy, and those who received no treatment were defined as EV, non-EV, and best supportive care (BSC) groups, respectively. The median OS was 20, 15, and 7 months in the EV, non-EV, and BSC groups, respectively (p < 0.001). Patients with la/mUC who had a complete or partial response after EV treatment had a significantly prolonged OS compared with those with stable or progressive disease. Univariate analysis showed age, neutrophil-to-lymphocyte ratio (NLR), dysgeusia, and rash as independent predictors of OS improvement. NLR and dysgeusia were independent predictors of OS after EV in multivariate analysis. Patients without these factors had a significantly prolonged OS compared to those with both factors. In real-world practice, EV therapy is an effective treatment for patients with la/mUC after ICI treatment. Full article

Prostate cancer is the most prevalent cancer among men in the United States and is a leading cause of cancer-related death. Prostate specific membrane antigen (PSMA) has been established as a biomarker for prostate cancer diagnosis and treatment. This study aimed to develop a novel theranostic agent, PSMA-1-MMAE-Pc413, which integrates a PSMA-targeting ligand, the photosensitizer Pc413, and the microtubular inhibitor monomethyl auristatin E (MMAE) for synergistic therapeutic efficacy. In vitro uptake studies revealed that PSMA-1-MMAE-Pc413 demonstrated selective and specific uptake in PSMA-positive PC3pip cells but not in PSMA-negative PC3flu cells, with the uptake in PC3pip cells being approximately three times higher. In vitro cytotoxicity assays showed that, when exposed to light, PSMA-1-MMAE-Pc413 had a synergistic effect, leading to significantly greater cytotoxicity in PSMA-positive cells (IC₅₀ = 2.2 nM) compared to PSMA-1-Pc413 with light irradiation (IC₅₀ = 164.9 nM) or PSMA-1-MMAE-Pc413 without light irradiation (IC₅₀ = 12.6 nM). In vivo imaging studies further demonstrated the selective uptake of PSMA-1-MMAE-Pc413 in PC3pip tumors. In in vivo studies, PSMA-1-MMAE-Pc413 dramatically improves the therapeutic outcome for prostate cancer by providing a synergistic effect that surpasses the efficacy of each treatment modality alone in PC3pip tumors. These findings suggest that PSMA-1-MMAE-Pc413 has strong potential for clinical application in improving prostate cancer treatment. Full article

An antibody–drug conjugate (ADC) targeting CD46 conjugated to monomethyl auristatin has a potent anti-myeloma effect in cell lines in vitro and in vivo, and patient samples treated ex vivo. Here, we tested if CD46–ADC may have the potential to target MM-initiating cells (MM-ICs). CD46 expression was measured on primary MM cells with a stem-like phenotype. A patient-derived xenograft (PDX) model was implemented utilizing implanted fetal bone fragments to provide a humanized microenvironment. Engraftment was monitored via serum human light chain ELISA, and at sacrifice via bone marrow and bone fragment flow cytometry. We then tested MM regeneration in PDX by treating mice with CD46–ADC or the nonbinding control–ADC. MM progenitor cells from patients that exhibit high aldehyde dehydrogenase activity also have a high expression of CD46. In PDX, newly diagnosed MM patient samples engrafted significantly more compared to relapsed/refractory samples. In mice transplanted with newly diagnosed samples, CD46–ADC treatment showed significantly decreased engraftment compared to control–ADC treatment. Our data further support the targeting of CD46 in MM. To our knowledge, this is the first study to show preclinical drug efficacy in a PDX model of MM. This is an important area for future study, as patient samples but not cell lines accurately represent intratumoral heterogeneity. Full article

High numbers of membrane immunoglobulin E (IgE)-positive cells are characteristic of allergic conditions, atopic dermatitis, or IgE myeloma. Antibodies targeting the extracellular membrane-proximal domain of the membranous IgE-B-cell receptor (BCR) fragment can be used for specific depletion of IgE-BCR-positive cells. In this study, we derivatized such an antibody with a toxin and developed an antibody–drug conjugate (ADC) that showed strong cytotoxicity for an IgE-positive target cell line. Site-specific conjugation with maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl-monomethyl-auristatin E via a newly introduced single cysteine residue was used to prepare a compound with a drug–antibody ratio of 2 and favorable biophysical properties. The antibody was rapidly taken up by the target cells, showing almost complete internalization after 4 h of treatment. Its cytotoxic effect was potentiated upon cross-linking mediated by an anti-human IgG F(ab’)₂ fragment. Because of its fast internalization and strict target specificity, this antibody–drug conjugate presents a valuable starting point for the further development of an anti-IgE cell-depleting agent, operating by the combined action of receptor cross-linking and toxin-mediated cytotoxicity. Full article

Non-small cell lung cancer (NSCLC) patients, accounting for approximately 85% of lung cancer cases, are usually diagnosed in advanced stages. Traditional surgical resection and radiotherapy have very limited clinical benefits. The objective of this study was to develop and evaluate a targeted therapy, antibody-drug conjugate (ADC), for NSCLC treatment. Specifically, the CD276 receptor was evaluated and confirmed as an ideal surface target of NSCLC in the immunohistochemistry (IHC) staining of seventy-three patient tumor microarrays and western blotting analysis of eight cell lines. Our anti-CD276 monoclonal antibody (mAb) with cross-activity to both human and mouse receptors showed high surface binding, effective drug delivery and tumor-specific targeting in flow cytometry, confocal microscopy, and in vivo imaging system analysis. The ADC constructed with our CD276 mAb and payload monomethyl auristatin F (MMAF) showed high anti-NSCLC cytotoxicity to multiple lines and effective anti-tumor efficacy in both immunocompromised and immunocompetent NSCLC xenograft mouse models. The brief mechanism study revealed the integration of cell proliferation inhibition and immune cell reactivation in tumor microenvironments. The toxicity study did not detect off-target immune toxicity or peripheral toxicity. Altogether, this study suggested that anti-CD276 ADC could be a promising candidate for NSCLC treatment. Full article

Antibody–drug conjugates (ADCs) are at the forefront of the drug development revolution occurring in oncology. Formed from three main components—an antibody, a linker molecule, and a cytotoxic agent (“payload”), ADCs have the unique ability to deliver cytotoxic agents to cells expressing a specific antigen, a great leap forward from traditional chemotherapeutic approaches that cause widespread effects without specificity. A variety of payloads can be used, including most frequently microtubular inhibitors (auristatins and maytansinoids), as well as topoisomerase inhibitors and alkylating agents. Finally, linkers play a critical role in the ADCs’ effect, as cleavable moieties that serve as linkers impact site-specific activation as well as bystander killing effects, an upshot that is especially important in solid tumors that often express a variety of antigens. While ADCs were initially used in hematologic malignancies, their utility has been demonstrated in multiple solid tumor malignancies, including breast, gastrointestinal, lung, cervical, ovarian, and urothelial cancers. Currently, six ADCs are FDA-approved for the treatment of solid tumors: ado-trastuzumab emtansine and trastuzumab deruxtecan, both anti-HER2; enfortumab-vedotin, targeting nectin-4; sacituzuzmab govitecan, targeting Trop2; tisotumab vedotin, targeting tissue factor; and mirvetuximab soravtansine, targeting folate receptor-alpha. Although they demonstrate utility and tolerable safety profiles, ADCs may become ineffective as tumor cells undergo evolution to avoid expressing the specific antigen being targeted. Furthermore, the current cost of ADCs can be limiting their reach. Here, we review the structure and functions of ADCs, as well as ongoing clinical investigations into novel ADCs and their potential as treatments of solid malignancies. Full article

Antibody-drug conjugates (ADCs) have demonstrated a great therapeutic potential against cancer due to their target specificity and cytotoxicity. To exert a maximum therapeutic effect on cancerous cells, we have conjugated two different payloads to different amino acids, cysteines (cys) and lysines (lys), on trastuzumab, which is a humanised anti-HER2 monoclonal antibody. First, trastuzumab was conjugated with monomethyl auristatin E (MMAE), an antimitotic agent, through a cleavable linker (Val-Cit) to prepare ADC (Tmab-VcMMAE). Then, the ADC (Tmab-VcMMAE) was conjugated with a second antimitotic agent, Mertansine (DM1), via a non-cleavable linker Succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) to form a dual conjugate (Tmab-VcMMAE-SMCC-DM1). Our results indicated that the dual-payload conjugate, Tmab-VcMMAE-SMCC-DM1, had a synergistic and superior cytotoxic effect compared to trastuzumab alone. Ultimately employing a dual conjugation approach has the potential to overcome treatment-resistance and tumour recurrences and could pave the way to employ other payloads to construct dual (or multiple) payload complexes. Full article