scholarly journals In Silico Designing of a Novel Antibody Conjugate as a Potential Immunotherapeutic for the Treatment of CD19-Positive Hematologic Malignancies

2021 ◽  
Vol 1 (2) ◽  
Author(s):  
Pooria Safarzadeh Kozani
Keyword(s):  
Cancer Treatment ◽  
In Silico ◽  
Binding Capacity ◽  
3D Structure ◽  
Hematologic Malignancies ◽  
Cytotoxic Agents ◽  
Single Chain ◽  
Drug Conjugates ◽  
Linker Peptide ◽  
Antibody Conjugate

Background: Immunotherapy can now be considered as game changer of cancer treatment. So far, numerous monoclonal antibodies (mAbs) and their derivatives, such as antibody-drug conjugates (ADCs), have been approved by regulatory agencies for medical use. This implies that the recombinant or chemical conjugation of mAbs to cytotoxic agents can be regarded as a potential cancer treatment modality. Objectives: This study aimed to design an antibody conjugate through the recombinant conjugation of a humanized CD19-specific single-chain variable fragment (scFv), named HuFMC63, to granzyme B (GrB) using precise in silico approaches. Methods: Four different linker peptides were used for the conjugation of HuFMC63 to GrB, and the 3D structure of these antibody conjugates were predicted using GalaxyWEB. The antibody conjugate whose linker peptide had the least impact on the structural conformation of HuFMC63 and GrB was subsequently selected. Additionally, the solubility and melting temperature of the selected conjugate was compared with those of HuFMC6 and GrB, and its physicochemical properties and flexibility were also assessed. Ultimately, the binding capacity and the dissociation constant (Kd) of the selected conjugate to CD19 were compared with those of HuFMC63 (concisely referred to as Hu63), and then the residues that contributed to antigen binding were identified using LigPlot+ software. Results: The Hu63-(G4S)3-GrB conjugate, which is constructed using the (G4S)3 linker, was selected as the best conjugate. The solubility of Hu63-(G4S)3-GrB was predicted to be higher than HuFMC63 and GrB (from 60% in the unconjugated to 98% in the conjugated format). Moreover, it was elucidated that Hu63-(G4S)3-GrB binds CD19 in the same orientation as that of HuFMC63 and with the same Kd of 17 and 33 nM at 25.0°C and 37.0°C, respectively. Conclusions: In silico techniques, such as those employed in this study, could be utilized for the early development of immune-based therapeutics. Moreover, Hu63-(G4S)3-GrB could be introduced as a potent therapeutic for the elimination of CD19-positive malignant cells after careful preclinical and clinical evaluations.

Antibody-Drug Conjugates in Hematologic Malignancies

2013 ◽  
pp. e108-e113
Author(s):  
Lori A. Leslie ◽  
Anas Younes
Keyword(s):  
Hematologic Malignancies ◽  
Cytotoxic Agents ◽  
Clinical Value ◽  
Suppressor Activity ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Tumor Suppressor Activity ◽  
Cytotoxic Molecules ◽  
Early Phase Clinical Trials ◽  
Antibody Drug

Antibody-drug conjugates (ADCs) are agents composed of a monoclonal antibody linked to cytotoxic molecules. By specifically delivering cytotoxic agents to cells expressing surface antigens of interest, ADC technology allows for the targeted use of highly toxic agents resulting in increased efficacy against malignant cells and decreased damage to normal tissue. Effector agents can be small molecules, radioisotopes, proteins, or bacterially derived toxins. Over the past several decades, ADCs have been evaluated in a variety of preclinical models of hematologic malignancies, as well as early-phase clinical trials with limited success. More recently, advancements in linkage technology, improvements in cytotoxin selection, and use of smaller conjugates containing partial rather than complete antibodies have drastically improved the potential clinical value of ADCs. In the future, ADC technology may be used to restore tumor suppressor activity, target the microenvironment, or replace nonfunctional enzymes. In this review we will discuss select ADCs in various stages of development for use in hematologic malignancies including lymphoma, multiple myeloma, and leukemia.

Antibody-drug conjugates: Principles and clinical results in breast cancer treatment

2018 ◽  
Vol 39 (4) ◽  
pp. 490-495
Author(s):  
Nguyen Phuong Loan ◽  
Duong Hong Quan
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Safety Data ◽  
Clinical Results ◽  
Breast Cancer Treatment ◽  
Surface Proteins ◽  
Cytotoxic Agents ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

Antibody-drug conjugates (ADCs) are consisted of the combination of highly specific monoclonal antibodies (mAbs) with conventional cytotoxic agents to particular cancer types. The use of mAbs that are specific to tumor cell-surface proteins allows highly selective accumulation of cytotoxic agents as ADCs at the tumor tissue, that is not achievable with conventional cytotoxic agents alone. Designing of effective ADCs for cancer treatment requires identification of an appropriate target, a mAb against the target, potent cytotoxic agents and conjugation of the mAb to cytotoxic agents. Until now, three ADCs including Gemtuzumab ozogamicin, Brentuximab and trastuzumab emtansine have received an FDA approval so far. These three ADCs have shown improved efficacy and safety data compared with standard chemotherapy for the treatment of patients of acute myeloid leukemia, advanced lymphoma and breast cancer, respectively. Moreover, several promising ADCs are now in the latter-phase of clinical testing. Thus, with special focusing on these new anti-cancer drugs, this review briefly describes the principles of ADCs including their structure and mechanism of action, and summarizes their clinical performance in breast cancer. Citation: Nguyen Phuong Loan, Duong Hong Quan, 2017. Antibody-drug conjugates: Principles and clinical results in breast cancer treatment. Tap chi Sinh hoc, 39(4): 489-493. DOI: 10.15625/0866-7160/v39n4.9327.*Corresponding author: [email protected] 15 March 2017, accepted 12 December 2017

scholarly journals Drug Combination in Cancer Treatment—From Cocktails to Conjugated Combinations

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 669
Author(s):  
Yosi Gilad ◽  
Gary Gellerman ◽  
David M. Lonard ◽  
Bert W. O’Malley
Keyword(s):  
Drug Treatment ◽  
Cancer Treatment ◽  
Drug Combination ◽  
Drug Combinations ◽  
Cytotoxic Agents ◽  
Small Molecule Drug ◽  
Drug Conjugates ◽  
Future Improvement ◽  
Combinational Treatment ◽  
Selective Delivery

It is well recognized today that anticancer drugs often are most effective when used in combination. However, the establishment of chemotherapy as key modality in clinical oncology began with sporadic discoveries of chemicals that showed antiproliferative properties and which as a first attempt were used as single agents. In this review we describe the development of chemotherapy from its origins as a single drug treatment with cytotoxic agents to polydrug therapy that includes targeted drugs. We discuss the limitations of the first chemotherapeutic drugs as a motivation for the establishment of combined drug treatment as standard practice in spite of concerns about frequent severe, dose limiting toxicities. Next, we introduce the development of targeted treatment as a concept for advancement within the broader field of small-molecule drug combination therapy in cancer and its accelerating progress that was boosted by recent scientific and technological progresses. Finally, we describe an alternative strategy of drug combinations using drug-conjugates for selective delivery of cytotoxic drugs to tumor cells that potentiates future improvement of drug combinations in cancer treatment. Overall, in this review we outline the development of chemotherapy from a pharmacological perspective, from its early stages to modern concepts of using targeted therapies for combinational treatment.

Aromatase Inhibitors for the Treatment of Breast Cancer: A Journey from the Scratch

2020 ◽  
Vol 20 (17) ◽  
pp. 1994-2004 ◽  
Author(s):  
Pooja Ratre ◽  
Keerti Mishra ◽  
Amit Dubey ◽  
Amber Vyas ◽  
Akhlesh Jain ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Treatment ◽  
Postmenopausal Women ◽  
Aromatase Inhibitors ◽  
3D Structure ◽  
Postmenopausal Breast Cancer ◽  
Breast Cancer Treatment ◽  
Third Generation ◽  
Breast Cancer Chemotherapy

Background: Estrogens are essential for the growth of breast cancer in the case of premenopausal as well as in postmenopausal women. However, most of the breast cancer incidences are reported in postmenopausal women and the concurrent risk surges with an increase in age. Since the enzyme aromatase catalyses essential steps in estrogen biosynthesis, Aromatase Inhibitors (AIs) are effective targeted therapy in patients with Estrogen Receptor positive (ER+) breast cancer. AIs are more effective than Selective Estrogen Receptor Modulators (SERMs) because they block both the genomic and nongenomic activities of ER. Till date, first, second and third-generation AIs have been approved by the FDA. The third-generation AIs, viz. Letrozole, Anastrozole, Exemestane, are currently used in the standard treatment for postmenopausal breast cancer. Methods: Data were collected from Medline, PubMed, Google Scholar, Science Direct through searching of keywords: ‘aromatase’, ‘aromatase inhibitors’, ‘breast cancer’, ‘steroidal aromatase inhibitors’, ‘non-steroidal inhibitors’ and ‘generations of aromatase inhibitors’. Results: In the current scenario of breast cancer chemotherapy, AIs are the most widely used agents which reveal optimum efficacy along with the least side effects. Keeping in view the prominence of AIs in breast cancer therapy, this review covered the detailed description of aromatase including its role in the biosynthesis of estrogen, biochemistry, gene expression, 3D-structure, and information of reported AIs along with their role in breast cancer treatment. Conclusion: AIs are the mainstream solution of the ER+ breast cancer treatment regimen with the continuous improvement of human understanding of the importance of a healthy life of women suffering from breast cancer.

scholarly journals Toward Homogenous Antibody Drug Conjugates Using Enzyme-Based Conjugation Approaches

2021 ◽  
Vol 14 (4) ◽  
pp. 343
Author(s):  
Ahmad Fawzi Hussain ◽  
Armin Grimm ◽  
Wenjie Sheng ◽  
Chaoyu Zhang ◽  
Marwah Al-Rawe ◽  
...  
Keyword(s):  
Therapeutic Agents ◽  
Amino Acid Residues ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Site Specific ◽  
Drug Conjugates ◽  
Complement Dependent Cytotoxicity ◽  
Antibody Conjugates ◽  
Specific Antigens ◽  
Antibody Conjugate ◽  
Therapeutic Mechanisms

In the last few decades, antibody-based diagnostic and therapeutic applications have been well established in medicine and have revolutionized cancer managements by improving tumor detection and treatment. Antibodies are unique medical elements due to their powerful properties of being able to recognize specific antigens and their therapeutic mechanisms such as blocking specific pathways, antibody-dependent cellular cytotoxicity, and complement-dependent cytotoxicity. Furthermore, modification techniques have paved the way for improving antibody properties and to develop new classes of antibody-conjugate-based diagnostic and therapeutic agents. These techniques allow arming antibodies with various effector molecules. However, these techniques are utilizing the most frequently used amino acid residues for bioconjugation, such as cysteine and lysine. These bioconjugation approaches generate heterogeneous products with different functional and safety profiles. This is mainly due to the abundance of lysine and cysteine side chains. To overcome these limitations, different site-direct conjugation methods have been applied to arm the antibodies with therapeutic or diagnostics molecules to generate unified antibody conjugates with tailored properties. This review summarizes some of the enzyme-based site-specific conjugation approaches.

scholarly journals CAR-T in Cancer Treatment: Develop in Self-Optimization, Win-Win in Cooperation

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1955
Author(s):  
Feifei Guo ◽  
Jiuwei Cui
Keyword(s):  
T Cells ◽  
Cancer Treatment ◽  
Unmet Needs ◽  
Hematologic Malignancies ◽  
Limiting Factors ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell Therapy ◽  
Car T ◽  
Application Prospects

Despite remarkable achievements in the treatment of hematologic malignancies, chimeric antigen receptor (CAR)-T cell therapy still faces many obstacles. The limited antitumor activity and persistence of infused CAR-T cells, especially in solid tumors, are the main limiting factors for CAR-T therapy. Moreover, clinical security and accessibility are important unmet needs for the application of CAR-T therapy. In view of these challenges, many potentially effective solutions have been proposed and confirmed. Both the independent and combined strategies of CAR-T therapy have exhibited good application prospects. Thus, in this review, we have discussed the cutting-edge breakthroughs in CAR-T therapy for cancer treatment, with the aim of providing a reference for addressing the current challenges.

scholarly journals Antibody–Drug Conjugates for the Treatment of Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2898
Author(s):  
Chiara Corti ◽  
Federica Giugliano ◽  
Eleonora Nicolò ◽  
Liliana Ascione ◽  
Giuseppe Curigliano
Keyword(s):  
Breast Cancer ◽  
Bystander Effect ◽  
Metastatic Breast ◽  
Therapeutic Index ◽  
Cytotoxic Agents ◽  
Target Antigen ◽  
Her2 Positive ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

Metastatic breast cancer (BC) is currently an incurable disease. Besides endocrine therapy and targeted agents, chemotherapy is often used in the treatment of this disease. However, lack of tumor specificity and toxicity associated with dose exposure limit the manageability of cytotoxic agents. Antibody–drug conjugates (ADCs) are a relatively new class of anticancer drugs. By merging the selectivity of monoclonal antibodies with the cytotoxic properties of chemotherapy, they improve the therapeutic index of antineoplastic agents. Three core components characterize ADCs: the antibody, directed to a target antigen; the payload, typically a cytotoxic agent; a linker, connecting the antibody to the payload. The most studied target antigen is HER2 with some agents, such as trastuzumab deruxtecan, showing activity not only in HER2-positive, but also in HER2-low BC patients, possibly due to a bystander effect. This property to provide a cytotoxic impact also against off-target cancer cells may overcome the intratumoral heterogeneity of some target antigens. Other cancer-associated antigens represent a strategy for the development of ADCs against triple-negative BC, as shown by the recent approval of sacituzumab govitecan. In this review, we discuss the current landscape of ADC development for the treatment of BC, as well as the possible limitations of this treatment.

scholarly journals Elucidating Binding Sites and Affinities of ERα Agonist and Antagonist to Human Alpha-Fetoprotein by in silico Modeling and Point Mutagenesis

2019 ◽  
Author(s):  
Nurbubu T. Moldogazieva ◽  
Daria S. Ostroverkhova ◽  
Nikolai N. Kuzmich ◽  
Vladimir V. Kadochnikov ◽  
Alexander A. Terentiev ◽  
...  
Keyword(s):  
Binding Sites ◽  
In Silico ◽  
Disulfide Bonds ◽  
Electrostatic Interactions ◽  
Molecular Mechanisms ◽  
3D Structure ◽  
Scoring Function ◽  
Alpha Fetoprotein ◽  
Ligand Interaction ◽  
Ligand Interactions

Alpha-fetoprotein (AFP) is a major embryo- and tumor-associated protein capable of binding and transporting variety of hydrophobic ligands including estrogens. AFP has been shown to inhibit estrogen receptor (ER)-positive tumor growth and this can be attributed to its estrogen-binding ability. Despite AFP has long been investigated, its three-dimensional (3D) structure has not been experimentally resolved and molecular mechanisms underlying AFP-ligand interaction remain obscure. In our study we constructed homology-based 3D model of human AFP (HAFP) with the purpose to perform docking of ERα ligands, three agonists (17β-estradiol, estrone and diethylstilbestrol) and three antagonists (tamoxifen, afimoxifene and endoxifen) into the obtained structure. Based on ligand docked scoring function, we identified three putative estrogen- and antiestrogen-binding sites with different ligand binding affinities. Two high-affinity sites were located in (i) a tunnel formed within HAFP subdomains IB and IIA and (ii) opposite side of the molecule in a groove originating from cavity formed between domains I and III, while (iii) the third low-affinity site was found at the bottom of the cavity. 100 ns MD simulation allowed studying their geometries and showed that HAFP-estrogen interactions occur due to van der Waals forces, while both hydrophobic and electrostatic interactions were almost equally involved in HAFP-antiestrogen binding. MM/GBSA rescoring method estimated binding free energies (ΔGbind) and showed that antiestrogens have higher affinities to HAFP as compared to estrogens. We performed in silico point substitutions of amino acid residues to confirm their roles in HAFP-ligand interactions and showed that Thr132, Leu138, His170, Phe172, Ser217, Gln221, His266, His316, Lys453, and Asp478 residues along two disulfide bonds, Cys224-Cys270 and Cys269-Cys277 have key roles in both HAFP-estrogen and HAFP-antiestrogen binding. Data obtained in our study contribute to understanding mechanisms underlying protein-ligand interactions and anti-cancer therapy strategies based on ER-binding ligands.

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