Antibody-drug conjugates (ADCs) targeting trophoblast cell surface antigen 2 (Trop-2) and precision treatment of breast cancer.
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ABSTRACT:
SUBMITTER: Stenvang J
PROVIDER: S-EPMC9708494 | biostudies-literature | 2022 Nov
REPOSITORIES: biostudies-literature
Publications
Antibody-drug conjugates (ADCs) targeting trophoblast cell surface antigen 2 (Trop-2) and precision treatment of breast cancer.
Stenvang Jan J Vestlev Peter Michael PM Jensen Benny Vittrup BV Pfeiffer Per P
Annals of translational medicine 20221101 21
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Project description: Not available
| S-EPMC9577799 | biostudies-literature
Project description:Antibody drug conjugates (ADCs) combine the potent cytotoxicity of chemotherapy with the antigen -specific targeted approach of antibodies into one single molecule. Trophoblast cell surface antigen 2 (TROP-2) is a transmembrane glycoprotein involved in calcium signal transduction and is expressed in multiple tumor types. TROP-2 expression is higher in HER2-negative breast tumors (HR+/HR-) and is associated with worse survival. Sacituzumab govitecan (SG) is a first-in-class TROP-2-directed ADC with an anti-TROP-2 antibody conjugated to SN-38, a topoisomerase inhibitor via a hydrolysable linker. This hydrolysable linker permits intracellular and extracellular release of the membrane permeable payload enabling the "bystander effect" contributing to the efficacy of this agent. There was significant improvement in progression free survival (PFS) and overall survival (OS) with SG versus chemotherapy in pretreated metastatic triple negative breast cancer (TNBC), resulting in regulatory approval. Common adverse events (AE) reported were neutropenia and diarrhea. SG also demonstrated clinical activity versus chemotherapy in a phase III trial of HR+/HER2-metastatic breast cancer (MBC) and is under evaluation in first-line metastatic and early stage TNBC as well. Datopotamab deruxtecan (Dato-DXd) is a TROP-2 ADC that differs from SG in that it has a cleavable tetrapeptide linker and a more potent topoisomerase inhibitor payload. This construct is highly stable in circulation with a longer half-life than SG, and undergoes cleavage in presence of intracellular lysosomal proteases. Dato-DXd demonstrated preliminary efficacy in unselected metastatic TNBC, with common AEs of low-grade nausea and stomatitis. Dato-DXd is being investigated in phase III studies in metastatic TNBC and HR+/HER2- MBC. These novel TROP-2 ADCs have the potential to deliver enhanced efficacy with reduced toxicity in MBC and possibly in early stage breast cancer (EBC).
| S-EPMC9614644 | biostudies-literature
Project description:Although breast cancer has a good prognosis compared with various cancers, metastatic breast cancer has an aggressive disease course and remains incurable. Therefore, treatment of early breast cancer to prevent recurrence and metastasis is crucial. Recently, the development of anti-cancer drugs, such as targeted agents and immuno-oncology, has been accelerating. Antibody-drug conjugates (ADCs) are also building a new paradigm. Particularly, ADCs targeting Trop-2 were approved for their efficacy in metastatic triple-negative breast cancer patients who received ≥2 prior systemic therapies and showed significant results in heavily pretreated hormone receptor-positive/HER2-negative breast cancer. In this brief review, we provide an overview of ongoing clinical trials of ADCs targeting Trop-2 in early breast cancer, specifically sacituzumab govitecan.
| S-EPMC9634352 | biostudies-literature
Project description:Cancer treatment has been founded traditionally on the three approaches of surgery, radiation, and chemotherapy with the latter recognized as the obvious systemic treatment approach applicable to disease that has spread. Although significant progress has been made over nearly 100 years of developing systemic treatments, it remains clear that use of the toxic agents involved is a two-edged sword with normal organ toxicities always needing to be balanced with and against administration of relevant therapeutic doses. With the advent of monoclonal antibodies targeted against tumor-associated antigens that could be used as carriers of potently toxic chemotherapy drugs, it was thought that such antibody-drug conjugates (ADCs) could engender the answer to the toxicity/therapeutic equation by shifting the equation more toward beneficial therapeutic efficacy. However, over 40 or so years, antibody-drug conjugates have not significantly affected the toxicity/therapy balance paradigm in most cancer indications, especially in solid tumors. Ideally, a further step may be required in that a non-tumor-targeted antibody-drug conjugate should be essentially nontoxic in its native administered form, with toxic effects unleashed only at the site of targeted tumors. A new approach that employs this principle is the use of an antibody-drug conjugate that is essentially nontoxic to normal tissues by virtue of requiring an extra step of light activation to become potent. We describe the preclinical data and first clinical results gained over the past few years by use of antibody-drug conjugates wherein the drug comprises a near-infrared photoactivatable dye delivered to tumors by a monoclonal antibody and is subsequently activated to a toxic entity solely at sites of tumors.
| S-EPMC7414968 | biostudies-literature
Project description:Antibody-drug conjugates (ADCs) that exploit the active metabolite SN-38, which is derived from the popular anticancer drug, irinotecan (a camptothecin that inhibits the nuclear topoisomerase I enzyme, inducing double-stranded DNA breaks during the mitotic S-phase of affected cells), represent a substantial advance in the ADC field. SN-38 has been conjugated to a humanized antibody against trophoblast cell surface antigen 2 (TROP-2), which is involved in cancer signaling pathways and has increased expression by many cancer cell types, yielding the ADC sacituzumab govitecan. By conjugating a higher number of SN-38 molecules to the immunoglobulin (drug-to-antibody ratio = 7-8:1), and giving higher (10 mg/kg) and repeated therapy cycles (Days 1 and 8 of 21-day cycles), enhanced drug uptake by the targeted cancer cells is achieved. Based on a unique conjugation method, the lactone ring of the SN-38 molecule is stabilized and the molecule is protected from glucuronidation, a process that contributes to the untoward late diarrhea experienced with irinotecan. Finally, while the ADC is internalized, the use of a moderately stable linker permits release of SN-38 in an acidic environment of the tumor cell and its microenvironment, contributing to a bystander effect on neighboring cancer cells. Here, we discuss the development of sacituzumab govitecan and clinical results obtained using it for the management of patients with advanced, refractive breast, lung, and urinary bladder cancers. Sacituzumab govitecan, which is undergoing accelerated approval review by the US Food and Drug Administration while also being studied in Phase 3 clinical studies, was granted Breakthrough Therapy status from the FDA for advanced, refractory, metastatic triple-negative breast cancer patients.
| S-EPMC6748572 | biostudies-literature
Project description:The primary purpose of ADCs is to increase the efficacy of anticancer medications by minimizing systemic drug distribution and targeting specific cells. Antibody conjugates (ADCs) have changed the way cancer is treated. However, because only a tiny fraction of patients experienced long-term advantages, current cancer preclinical and clinical research has been focused on combination trials. The complex interaction of ADCs with the tumor and its microenvironment appear to be reliant on the efficacy of a certain ADC, all of which have significant therapeutic consequences. Several clinical trials in various tumor types are now underway to examine the potential ADC therapy, based on encouraging preclinical results. This review tackles the potential use of ADCs in cancer therapy, emphasizing the essential processes underlying their positive therapeutic impacts on solid and hematological malignancies. Additionally, opportunities are explored to understand the mechanisms of ADCs action, the mechanism of resistance against ADCs, and how to overcome potential resistance following ADCs administration. Recent clinical findings have aroused interest, leading to a large increase in the number of ADCs in clinical trials. The rationale behind ADCs, as well as their primary features and recent research breakthroughs, will be discussed. We then offer an approach for maximizing the potential value that ADCs can bring to cancer patients by highlighting key ideas and distinct strategies.
| S-EPMC9375290 | biostudies-literature
Project description:Drug conjugates have been studied extensively in preclinical in vitro and in vivo models but to date only a few compounds have progressed to the clinical setting. This situation is now changing with the publication of studies demonstrating a significant impact on clinical practice and highlighting the potential of this new class of targeted therapies. This review summarizes the pharmacological and molecular background of the main drug conjugation systems, namely antibody drug conjugates (ADCs), immunotoxins and immunoliposomes. All these compounds combine the specific targeting moiety of an antibody or similar construct with the efficacy of a toxic drug. The aim of this strategy is to target tumor cells specifically while sparing normal tissue, thus resulting in high efficacy and low toxicity. Recently, several strategies have been investigated in phase I clinical trials and some have entered phase III clinical development. This review provides a detailed overview of various strategies and critically discusses the most relevant achievements. Examples of the most advanced compounds include T-DM1 and brentuximab vedotin. However, additional promising strategies such as immunotoxins and immunoliposmes are already in clinical development. In summary, targeted drug delivery by drug conjugates is a new emerging class of anti-cancer therapy that may play a major role in the future.
| S-EPMC3546676 | biostudies-other
Project description:The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a family of sequence-selective DNA minor-groove binding agents that form a covalent aminal bond between their C11-position and the C2-NH2 groups of guanine bases. The first example of a PBD monomer, the natural product anthramycin, was discovered in the 1960s, and the best known PBD dimer, SJG-136 (also known as SG2000, NSC 694501 or BN2629), was synthesized in the 1990s and has recently completed Phase II clinical trials in patients with leukaemia and ovarian cancer. More recently, PBD dimer analogues are being attached to tumor-targeting antibodies to create antibody-drug conjugates (ADCs), a number of which are now in clinical trials, with many others in pre-clinical development. This Review maps the development from anthramycin to the first PBD dimers, and then to PBD-containing ADCs, and explores both structure-activity relationships (SARs) and the biology of PBDs, and the strategies for their use as payloads for ADCs.
| S-EPMC5215561 | biostudies-literature
Project description:Background: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Sacituzumab govitecan (SG) is a novel antibody-drug-conjugate (ADC) targeting trophoblast-antigen-2 (Trop-2), a cell surface glycoprotein highly expressed in many epithelial tumors, to deliver SN-38, the active metabolite of irinotecan. This study aimed to evaluate Trop-2 expression in EOC tissues and the preclinical activity of SG against primary EOC cell lines and xenografts. Methods: Trop-2 expression was assessed in 90 formalin-fixed-paraffin-embedded tumors and nine primary tumor cell lines by immunohistochemistry (IHC) and flow cytometry, respectively. Trop-2 expression and cell viability after exposure to SG in primary tumor cell lines, non-targeting control ADC, and SG-parental antibody hRS7 were evaluated using flow-cytometry-based-assays. Antibody-dependent-cell-cytotoxicity (ADCC) against Trop-2+ and Trop-2- EOC cell lines was tested in vitro using 4 h Chromium-release-assays. In vivo activity of SG was evaluated against Trop-2+ EOC xenografts. Results: Moderate-to-strong staining was seen in 47% (42/90) of ovarian tumors by IHC while 89% (8/9) of the primary EOC cell lines overexpressed Trop-2 by flow cytometry. EOC Trop-2+ were significantly more sensitive to SG compared to control ADC (p < 0.05). Both SG and hRS7 mediated high ADCC activity against Trop-2+ cell lines. SG also induced significant bystander killing of Trop-2- tumor cells admixed with Trop-2+ EOC cells. In in vivo experiments SG treatment demonstrated impressive anti-tumor activity against chemotherapy-resistant EOC xenografts. Conclusion: SG demonstrates remarkable preclinical activity against biologically aggressive and chemotherapy-resistant EOC cell lines and a significant bystander effect against EOC cell lines with heterogenous Trop-2 expression. Clinical trials are warranted.
| S-EPMC7028697 | biostudies-literature
Project description:PurposeWithout a standard test for pancreatic carcinomas, this highly lethal disease is normally diagnosed at its advanced stage, leading to a low survival rate of patients. Trophoblast cell-surface antigen 2 (Trop-2), a transmembrane glycoprotein, is associated with cell proliferation and highly expressed in most of solid epithelial tumors, including pancreatic cancer. A non-invasive method of imaging Trop-2 would greatly benefit clinical diagnosis and monitoring of pancreatic cancer. In the current study, 89Zr-labeled anti-Trop-2 antibody (AF650) was recruited for the systemic evaluation of Trop-2 as an immunoPET target for pancreatic cancer imaging.MethodsAF650 was conjugated with desferrioxamine (DFO) and then radiolabeled with 89Zr. Trop-2 expression levels were determined in three pancreatic cancer cell lines (BxPC-3, MIA PaCa-2, and AsPC-1) via western blot, flow cytometry, saturation binding assay, and immunofluorescence staining. The targeting capacity of 89Zr-DFO-AF650 was evaluated in mouse models with subcutaneous xenograft of pancreatic cancers via PET imaging and bio-distribution studies. In addition, a Trop-2-positive orthotopic cancer model was recruited for further validating the targeting specificity of 89Zr-DFO-AF650.ResultsBxPC-3 cells expressed high levels of Trop-2, while AsPC-1 and MIA PaCa-2 cells expressed low levels of Trop-2. Additionally, 89Zr-DFO-AF650 exhibited high specificity to Trop-2 in BxPC-3 cells (Kd = 22.34 ± 2.509 nM). In subcutaneous xenograft models, about 28.8 ± 7.63%ID/g tracer accumulated in the BxPC-3 tumors at 120 h post injection, which was much higher than those reaching MIA PaCa-2 (6.76 ± 2.08%ID/g) and AsPC-1 (3.51 ± 0.69%ID/g) tumors (n = 4). More importantly, 89Zr-DFO-AF650 could efficiently distinguish primary tumors in the orthotopic BxPC-3 cancer model, showing high correlation between PET imaging and bio-distribution and sensitivity.Conclusions89Zr-DFO-AF650 can be effectively used to detect pancreatic cancer via Trop-2-mediated immunoPET in vivo, clearly revealing the great potential of Trop-2-based non-invasive imaging in pancreatic cancer detection and treatment monitoring.
| S-EPMC8810666 | biostudies-literature