The transgenic chicken derived anti-CD20 monoclonal antibodies exhibits greater anti-cancer therapeutic potential with enhanced Fc effector functions

Monoclonal antibodies (mAbs), available for a range of diseases, including tumours, leukemia, and multiple sclerosis, are emerging as the fastest growing area of therapeutic drug development. The greatest advantage of therapeutic mAbs is their ability to bind with a high degree of specificity to target proteins involved in disease pathophysiology. In response, effector functions are triggered and these ameliorate the disease cascade. As an alternative to this reliance on effector functions, drugs can be conjugated to mAbs. The ability to target compounds to the site of pathology minimises the nonspecific side effects associated with systemic administration. In both instances, optimising the delivery, absorption, and distribution of the mAbs, whilst minimising potential side effects, remain the key hurdles to improved clinical outcomes. Novel delivery strategies are being investigated with more vigour in recent years, and nanoparticles are being identified as suitable vehicles. In conjunction with permitting a controlled release profile, nanoparticles protect the drug from degradation, reducing both the dose and frequency of administration. Moreover, these particles shield the patient from the immune complications associated with high dose mAb infusions or drug cytotoxicity. This review outlines recent advances in nanoparticle technology and how they may be of benefit as therapeutic mAb delivery/targeting vehicles.

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Novel humanized anti-CD20 monoclonal antibodies with unique germline VH and VL gene recruitment and potent effector functions

International Journal of Oncology ◽

10.3892/ijo_32_6_1263 ◽

1992 ◽

Vol 32 (6) ◽

pp. 1263-1274 ◽

Cited By ~ 8

Author(s):

Michio Nishida

Keyword(s):

Monoclonal Antibodies ◽

Effector Functions ◽

Gene Recruitment ◽

Anti Cd20 ◽

Potent Effector

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Inhibition of NF-Kb Cell Signaling and Induction of the Metastasis Suppressor and Immune Surveillance Cancer Gene RKIP Expression in B-NHL by the Novel Humanized BM-Ca Anti-CD20 Monoclonal Antibody: Implication in Chemo and Immune-Sensitization

Blood ◽

10.1182/blood.v112.11.2613.2613 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2613-2613

Author(s):

Mario I Vega ◽

Melisa Martinez-Paniagua ◽

Sara Huerta-Yepez ◽

Benjamin Bonavida

Keyword(s):

Monoclonal Antibody ◽

Monoclonal Antibodies ◽

Gene Product ◽

P38 Mapk ◽

Immune Surveillance ◽

Metastasis Suppressor ◽

Gene Products ◽

Cancer Gene ◽

Effector Functions ◽

Anti Cd20

Abstract Treatment of patients with relapsed or refractory low-grade follicular B-NHL lymphoma with rituximab has resulted in ~50% response rate. The mechanism underlying the failure of rituximab to affect the remaining 50% of the patients is not clear, though their tumors express CD20. The in vivo effector functions of rituximab include ADCC, CDC, and seldom apoptosis. In addition, we have reported that rituximab signals the cells and inhibits several intracellular cell survival pathways that are responsible for the immune and chemo-sensitizing effects of rituximab on resistant B-NHL cell lines (see review Jazirehi and Bonavida, Oncogene24:2121, 2005). The objective of this study was to develop novel and fully humanized anti-CD20 monoclonal antibodies with enhanced effector functions and molecular signaling that may potentiate their therapeutic efficacy. Novel humanized anti-CD20 monoclonal antibodies were derived from a chimerized form of murine anti-CD20 1K11791, shown to exert more important ADCC, CDC, and apoptotic activities as compared to rituximab (Nishida et al., Int J Oncol., 31:29, 2007). A representative humanized monoclonal antibody, BM-ca (Biomedics Inc., Tokyo, Japan) was used to examine its molecular cell signaling on a representative Ramos B-NHL cell line. The studies were also performed in parallel with rituximab treatment. Ramos cells were treated with various concentrations of BM-ca monoclonal antibody and it was found to inhibit cell proliferation in a concentration-dependent manner. The optimal concentration of BM-ca mAb (20–40 μg/ml) was used for further molecular analyses. Following treatment of Ramos with BM-ca mAb for 24 hours, cell lysates were assessed for the expression of various gene products by Western. Compared to untreated cells, treatment with BM-ca inhibited constitutively activated NF-kB as assessed by inhibition of phospho-p65, phospho-IkB-α, but not unphosphorylated forms. In addition, the NF-kB upstream kinase phospho-p38 MAPK was also inhibited. Inhibition of NF-kB and phospho-p38 MAPK resulted in downstream inhibition of the anti-apoptotic gene product Mcl-1 and induction of the proapototic gene products Bax and Bak. BM-ca significantly induced the expression of the metastasis suppressor and immune surveillance cancer gene product, Raf-1 kinase inhibitor protein (RKIP). RKIP has been shown to inhibition NF-kB activity and inhibition of NF-kB results downstream in the inhibition of the metastasis-inducer gene product Snail. Snail is a transcription factor that has been shown recently to negatively regulate the expression of RKIP (Beach et al, Oncogene27:2243, 2008). BM-ca inhibited Snail expression in Ramos cells. In comparison with rituximab, BM-ca showed qualitative and quantitative differences in the regulation of gene expression. These findings demonstrate that BM-ca triggers CD20-expressing B-NHL cells and results in significant alteration of several gene products that regulate chemo and immune-resistance and metastasis.

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Novel humanized anti-CD20 monoclonal antibodies with unique germline VH and VL gene recruitment and potent effector functions

International Journal of Oncology ◽

10.3892/ijo.32.6.1263 ◽

2008 ◽

Author(s):

Michio Nishida ◽

Keisuke Teshigawara ◽

Otsura Niwa ◽

Sadakazu Usuda ◽

Tetsuo Nakamura ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Effector Functions ◽

Gene Recruitment ◽

Anti Cd20 ◽

Potent Effector

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Phytochemical, Pharmacological Activities and Ayurvedic Significances of Magical Plant Mimosa pudica Linn

Mini-Reviews in Organic Chemistry ◽

10.2174/1570178617999200629155204 ◽

2020 ◽

Vol 17 ◽

Author(s):

Vijay Kumar

Keyword(s):

Therapeutic Potential ◽

Wide Spectrum ◽

Chemical Constituents ◽

Future Research ◽

Mimosa Pudica ◽

Pharmacological Activities ◽

Medicinal Uses ◽

Traditional Medicines ◽

Crude Extracts ◽

Anti Cancer

: Mimosa pudica Linn is an integrated part of Traditional Medicines Systems of India, China, Africa, Korea and America. It has been used from centuries in traditional medicines to cure different diseases like fever, diabetes, constipation, jaundice, ulcers, biliousness, and dyspepsia. It is an important ingredient of wide class of herbal formulations. To assess the scientific evidence for therapeutic potential of Mimosa pudica Linn and to identify the gaps for future research. The available information on the ethno-medicinal uses, phytochemistry, pharmacology and toxicology of Mimosa pudica Linn was collected via a library and electronic searches in Sci-Finder, Pub-Med, Science Direct, Google Scholar for the period, 1990 to 2020. In traditional medicinal systems, variety of ethno-medicinal applications of Mimosa pudica Linn has been noticed. Phytochemical investigation has resulted in identification of 40 well known chemical constituents, among which alkaloids, phenols and flavionoids are the predominant groups. The crude extracts and isolates have exhibited a wide spectrum of in vitro and in vivo pharmacological activities including anti-cancer, anti-inflammation, osteoporosis, neurological disorders, hypertension etc.. To quantify the Mimosa pudica Linn and its formulations, analytical techniques like HPLC and HPTLC has shown dominancy with good range of recovery and detection limit. Mimosa pudica Linn is the well-known herb since an ancient time. The pharmacological results supported some of the applications of Mimosa pudica Linn in traditional medicine systems. Perhaps, the predominance of alkaloids, phenols and flavionoids are responsible for the pharmacological activities the crude extracts and isolates of Mimosa pudica Linn. Further, there is need to isolate and evaluate the active chemical constituents of Mimosa pudica Linn having significant medicinal values. In future, it is important to study the exact mechanism associated with the phytochemicals of Mimosa pudica Linn especially on anti-cancer activities. Notably, toxicity studies on Mimosa pudica Linn are limited which are to be explored in future for the safe application of Mimosa pudica Linn and its formulations.

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The HGR motif is the antiangiogenic determinant of vasoinhibin: implications for a therapeutic orally active oligopeptide

Angiogenesis ◽

10.1007/s10456-021-09800-x ◽

2021 ◽

Author(s):

Juan Pablo Robles ◽

Magdalena Zamora ◽

Lourdes Siqueiros-Marquez ◽

Elva Adan-Castro ◽

Gabriela Ramirez-Hernandez ◽

...

Keyword(s):

Therapeutic Agent ◽

Clinical Evidence ◽

Therapeutic Potential ◽

Peripartum Cardiomyopathy ◽

Loss Of Function ◽

Functional Determinant ◽

Melanoma Tumor ◽

Linear Motif ◽

Anti Cancer ◽

Orally Active

AbstractThe hormone prolactin acquires antiangiogenic and antivasopermeability properties after undergoing proteolytic cleavage to vasoinhibin, an endogenous prolactin fragment of 123 or more amino acids that inhibits the action of multiple proangiogenic factors. Preclinical and clinical evidence supports the therapeutic potential of vasoinhibin against angiogenesis-related diseases including diabetic retinopathy, peripartum cardiomyopathy, rheumatoid arthritis, and cancer. However, the use of vasoinhibin in the clinic has been limited by difficulties in its production. Here, we removed this barrier to using vasoinhibin as a therapeutic agent by showing that a short linear motif of just three residues (His46-Gly47-Arg48) (HGR) is the functional determinant of vasoinhibin. The HGR motif is conserved throughout evolution, its mutation led to vasoinhibin loss of function, and oligopeptides containing this sequence inhibited angiogenesis and vasopermeability with the same potency as whole vasoinhibin. Furthermore, the oral administration of an optimized cyclic retro-inverse vasoinhibin heptapeptide containing HGR inhibited melanoma tumor growth and vascularization in mice and exhibited equal or higher antiangiogenic potency than other antiangiogenic molecules currently used as anti-cancer drugs in the clinic. Finally, by unveiling the mechanism that obscures the HGR motif in prolactin, we anticipate the development of vasoinhibin-specific antibodies to solve the on-going challenge of measuring endogenous vasoinhibin levels for diagnostic and interventional purposes, the design of vasoinhibin antagonists for managing insufficient angiogenesis, and the identification of putative therapeutic proteins containing HGR.

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Molecular and Biochemical Basis of Minocycline-Induced Hyperpigmentation—The Study on Normal Human Melanocytes Exposed to UVA and UVB Radiation

International Journal of Molecular Sciences ◽

10.3390/ijms22073755 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3755

Author(s):

Jakub Rok ◽

Zuzanna Rzepka ◽

Justyna Kowalska ◽

Klaudia Banach ◽

Artur Beberok ◽

...

Keyword(s):

Uv Radiation ◽

Therapeutic Potential ◽

Melanin Synthesis ◽

Uvb Radiation ◽

Biochemical Basis ◽

Skin Hyperpigmentation ◽

Human Melanocytes ◽

Anti Cancer ◽

Normal Human

Minocycline is a drug which induces skin hyperpigmentation. Its frequency reaches up to 50% of treated patients. The adverse effect diminishes the great therapeutic potential of minocycline, including antibacterial, neuroprotective, anti-inflammatory and anti-cancer actions. It is supposed that an elevated melanin level and drug accumulation in melanin-containing cells are related to skin hyperpigmentation. This study aimed to evaluate molecular and biochemical mechanism of minocycline-induced hyperpigmentation in human normal melanocytes, as well as the contribution of UV radiation to this side effect. The experiments involved the evaluation of cyto- and phototoxic potential of the drug using cell imaging with light and confocal microscopes as well as biochemical and molecular analysis of melanogenesis. We showed that minocycline induced melanin synthesis in epidermal melanocytes. The action was intensified by UV irradiation, especially with the UVB spectrum. Minocycline stimulated the expression of microphthalmia-associated transcription factor (MITF) and tyrosinase (TYR) gene. Higher levels of melanin and increased activity of tyrosinase were also observed in treated cells. Moreover, minocycline triggered the supranuclear accumulation of tyrosinase, similar to UV radiation. The decreased level of premelanosome protein PMEL17 observed in all minocycline-treated cultures suggests disorder of the formation, maturation or distribution of melanosomes. The study revealed that minocycline itself was able to enhance melanin synthesis. The action was intensified by irradiation, especially with the UVB spectrum. Demonstrated results confirmed the potential role of melanin and UV radiation minocycline-induced skin hyperpigmentation.

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Production of Recombinant Monoclonal Antibodies in the Egg White of Gene-Targeted Transgenic Chickens

Genes ◽

10.3390/genes12010038 ◽

2020 ◽

Vol 12 (1) ◽

pp. 38

Author(s):

Takehiro Mukae ◽

Sho Okumura ◽

Takuma Watanobe ◽

Kyoko Yoshii ◽

Takahiro Tagami ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Binding Capacity ◽

Specific Binding ◽

Egg White ◽

Peptide Sequence ◽

Efficient Production ◽

Antigen Binding ◽

Transgenic Chicken ◽

Bioreactor System ◽

Transgenic Chickens

Increased commercial demand for monoclonal antibodies (mAbs) has resulted in the urgent need to establish efficient production systems. We previously developed a transgenic chicken bioreactor system that effectively produced human cytokines in egg whites using genome-edited transgenic chickens. Here, we describe the application of this system to mAb production. The genes encoding the heavy and light chains of humanized anti-HER2 mAb, linked by a 2A peptide sequence, were integrated into the chicken ovalbumin gene locus using a CRISPR/Cas9 protocol. The knock-in hens produced a fully assembled humanized mAb in their eggs. The mAb expression level in the egg white was 1.4–1.9 mg/mL, as determined by ELISA. Furthermore, the antigen binding affinity of the anti-HER2 mAb obtained was estimated to be equal to that of the therapeutic anti-HER2 mAb (trastuzumab). In addition, antigen-specific binding by the egg white mAb was demonstrated by immunofluorescence against HER2-positive and -negative cells. These results indicate that the chicken bioreactor system can efficiently produce mAbs with antigen binding capacity and can serve as an alternative production system for commercial mAbs.

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Dietary Curcumin: Correlation between Bioavailability and Health Potential

Nutrients ◽

10.3390/nu11092147 ◽

2019 ◽

Vol 11 (9) ◽

pp. 2147 ◽

Cited By ~ 42

Author(s):

Michele Dei Cas ◽

Riccardo Ghidoni

Keyword(s):

Small Intestine ◽

Cellular Uptake ◽

Oral Delivery ◽

Therapeutic Potential ◽

Pharmacokinetic Profile ◽

Yellow Pigment ◽

The Body ◽

Anti Cancer ◽

Poor Absorption ◽

Oral Delivery Systems

The yellow pigment curcumin, extracted from turmeric, is a renowned polyphenol with a broad spectrum of health properties such as antioxidant, anti-inflammatory, anti-cancer, antidiabetic, hepatoprotective, anti-allergic, anti-dermatophyte, and neuroprotective. However, these properties are followed by a poor pharmacokinetic profile which compromises its therapeutic potential. The association of low absorption by the small intestine and the extensive reductive and conjugative metabolism in the liver dramatically weakens the oral bioavailability. Several strategies such as inhibition of curcumin metabolism with adjuvants as well as novel solid and liquid oral delivery systems have been tried to counteract curcumin poor absorption and rapid elimination from the body. Some of these drug deliveries can successfully enhance the solubility, extending the residence in plasma, improving the pharmacokinetic profile and the cellular uptake.

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Antigenic modulation limits the effector cell mechanisms employed by type I anti-CD20 monoclonal antibodies

Blood ◽

10.1182/blood-2014-07-588376 ◽

2015 ◽

Vol 125 (12) ◽

pp. 1901-1909 ◽

Cited By ~ 43

Author(s):

Thomas R. W. Tipton ◽

Ali Roghanian ◽

Robert J. Oldham ◽

Matthew J. Carter ◽

Kerry L. Cox ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Natural Killer Cell ◽

Natural Killer ◽

Effector Cell ◽

Killer Cell ◽

Type I ◽

Antigenic Modulation ◽

Effector Mechanism ◽

Key Points ◽

Anti Cd20

Key Points Antigenic modulation significantly impacts natural killer cell and macrophage ability to mediate Fc γ receptor-dependent killing. hIgG1 mAbs are unable to elicit natural killer–mediated ADCC in the mouse, supporting ADCP as the dominant effector mechanism.

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