• Biomolecules & Therapeutics
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• v.23 no.6
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• pp.493-509
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• 2015

Antibody-drug conjugates utilize the antibody as a delivery vehicle for highly potent cytotoxic molecules with specificity for tumor-associated antigens for cancer therapy. Critical parameters that govern successful antibody-drug conjugate development for clinical use include the selection of the tumor target antigen, the antibody against the target, the cytotoxic molecule, the linker bridging the cytotoxic molecule and the antibody, and the conjugation chemistry used for the attachment of the cytotoxic molecule to the antibody. Advancements in these core antibody-drug conjugate technology are reflected by recent approval of Adectris$^{(R)}$(anti-CD30-drug conjugate) and Kadcyla$^{(R)}$(anti-HER2 drug conjugate). The potential approval of an anti-CD22 conjugate and promising new clinical data for anti-CD19 and anti-CD33 conjugates are additional advancements. Enrichment of antibody-drug conjugates with newly developed potent cytotoxic molecules and linkers are also in the pipeline for various tumor targets. However, the complexity of antibody-drug conjugate components, conjugation methods, and off-target toxicities still pose challenges for the strategic design of antibody-drug conjugates to achieve their fullest therapeutic potential. This review will discuss the emergence of clinical antibody-drug conjugates, current trends in optimization strategies, and recent study results for antibody-drug conjugates that have incorporated the latest optimization strategies. Future challenges and perspectives toward making antibody-drug conjugates more amendable for broader disease indications are also discussed.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.1
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• pp.15-20
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• 2013

Urinary bladder squamous cell carcinoma (SCC), one of the most common neoplasms in Egypt, is attributed to chronic urinary infection with Schistosoma haematobium (Schistosomiasis). The proto-oncogene c-KIT, encoding a tyrosine kinase receptor and implicated in the development of a number of human malignancies, has not been studied so far in schistosomal urinary bladder SCCs. We therefore determined immunohistochemical (IHC) expression of c-KIT in paraffin sections from 120 radical cystectomies of SCCs originally obtained from the Pathology Department of Suez Canal University (Ismailia, Egypt). Each slide was evaluated for staining intensity where the staining extent of >10% of cells was considered positive. c-KIT overexpression was detected in 78.3% (94/120) of the patients, the staining extents in the tumor cells were 11-50% and >50% in 40 (42.6%) and 54 (57.4%) respectively. The positive cases had 14.9%, 63.8%, 21.3% as weak, moderate and strong intensity respectively. Patients with positive bilharzial ova had significantly higher c-KIT expression than patients without (95.2% vs. 38.9%, P=0.000). Mutation analysis of exons 9-13 was negative in thirty KIT positive cases. The high rate of positivity in SBSCC was one of the striking findings; However, CD117 may be a potential target for site specific immunotherapy to improve the outcome of this tumor.

• Journal of Biomedical Engineering Research
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• v.13 no.3
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• pp.181-188
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• 1992

This paper provides an overview of system analysis of immunology. The theoretical research in this area is aimed at an understanding of the precise manner by which the immune system controls Infec pious diseases, cancer, and AIDS. This can provide a systematic plan for immunological experimentation by means of an integrated program of immune system analysis, mathematical modeling and computer simulation. Biochemical reactions and cellular fission are naturally modeled as nonlinear dynamical processes to synthesize the human immune system! as well as the complete organism it is intended to protect. A foundation for the control of tumors is presented, based upon the formulation of a realistic, knowledge based mathematical model of the interaction between tumor cells and the immune system. Ordinary bilinear differential equations which are coupled by such nonlinear term as saturation are derived from the basic physical phenomena of cellular and molecular conservation. The parametric control variables relevant to the latest experimental data are also considered. The model consists of 12 states, each composed of first-order, nonlinear differential equations based on cellular kinetics and each of which can be modeled bilinearly. Finally, tumor control as an application of immunotherapy is analyzed from the basis established.

• Tuberculosis and Respiratory Diseases
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• v.57 no.4
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• pp.336-344
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• 2004

Background : Immunotherapy for cancer has not been successful because of several obstacles in tumor and its environment. Inappropriate secretions of cytokines and growth factors by tumors cause substantial changes in the immune responses against tumors, affording the tumors some degree of protection from immune attack. Uteroglobin (UG, Clara cell secretory protein) has been known to have anti-inflammatory, immunomodulatory and anti-cancer activities. However, in lung cancer cells, UG expression is decreased. This study investigated the role of UG in the immunomodulation of lung cancer. Methods : The UG protein was overexpressed by Adenovirus(Ad)-UG transduction in non-small cell lung cancer cell lines. The concentration of Prostaglandin $E_2$ ($PGE_2$) was measured by Enzyme Immunoassay (EIA). Peripheral blood mononuclear cells (PBMC) from whole blood were prepared with Ficoll. PBMC were cultured in RPMI 1640, supernatant of A549, or A549 with UG or NS-398. Concentration of Th 1 type and Th 2 type cytokines from PBMC were measured by ELISA. Results : UG suppressed $PGE_2$, Cyclooxygenase-2 (COX-2) product. Both Th1 type such as Interleukin-2 (IL-2), Interferon-${\gamma}$ (IFN-${\gamma}$) and Tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) and Th2 type cytokines such as IL-10 and Tumor growth factor-${\beta}$ (TGF-${\beta}$) were increased when PBMC were cultured with supernatant of non small lung cancer cells. UG and COX-2 inhibitor, NS-398 induced normal immune response of PBMC. Although Th 1 type cytokines were increased, Th 2 type cytokines were reduced by UG. Conclusion : UG suppressed PGE2, COX-2 product. Supernatant of NSCLC induced imbalance of immune response of PBMC. However, UG reversed this imbalance. These results suggest that UG may be used in the development of immunotherapy for lung cancer.

• Proceedings of the KOSOMBE Conference
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• v.1991 no.05
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• pp.82-85
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• 1991

Cell kinetics and the chemical mass action principle formulate the basis of immune system dynamics which may be synthesized mathematically as cascades of bilinear systems which are connected by nonlinear nondynamical terms. In this manner, a model for cell-mediated immune response (CMI) to tumor antigens and debris is developed. We also consider parametric control variables relevant to the latest experimental data, i.e., sigmoidal dose-response relationship and Michaelis-Menten dynamics. The preliminary results show that the parametric control variable is important in the destruction of tumors. As well as that, the exacerbation theory is a good method for tumor treatment. Finally, tumor control as an application of immunotherapy is analyzed from the basis established above.

• Biomedical Science Letters
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• v.18 no.3
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• pp.210-217
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• 2012

Oncolytic viral vectors have shown good candidates for cancer treatment but have many limitations. To improve the therapeutic potential of oncolytic vaccinia virus, we developed a recombinant vaccinia virus expressing the 4-1BBL co-stimulatory molecule or CCL21. 4-1BBL and CCL21 expression was identified by FACS analysis and immunoblotting. rV-4-1BBL vaccination shows significant tumor regression compared to rV-LacZ, but rV-CCL21 shows rapid tumor growth compared to rV-LacZ in the poorly immunogenic B16 murine melanoma model. 4-1BBL expression resulted in the increase of the number of CD8+ T cells and especially the increase of effector (CD62L-CD44+) CD8+ T cells. These data suggest 4-1BBL may be the potential target for enhancement of tumor immunotherapy.

• Nuclear Medicine and Molecular Imaging
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• v.41 no.1
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• pp.1-8
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• 2007

This review discusses the production of alpha-particle-emitting radionuclides in radioimmunotherapy. Radioimmunotherapy labeled with alpha-particle is expected to be very useful for the treatment of monocellular cancer (e.g. leukemia) and micrometastasis at an early stage, residual tumor remained in tissues after chemotherapy and tumor resection, due to the high linear energy transfer (LET) and the short path length in biological tissue of alpha particle. Despite of the expected effectiveness of alpha-particle in radioimmunotherapy, its clinical research has not been activated by the several reasons, shortage of a suitable a-particle development and a reliable radionuclide production and supply system, appropriate antibody and chelator development. Among them, the establishment of radionuclide development and supply system is a key factor to make an alpha-immunotherapy more popular in clinical trial. Alpha-emitter can be produced by several methods, natural radionuclides, reactor irradiation, cyclotron irradiation, generator system and elution. Due to the sharply increasing demand of $^{213}Bi$, which is a most promising radionuclide in radioimmunotherapy and now has been produced with reactor, the cyclotron production system should be developed urgently to meet the demand.

• Journal of Korean Physical Therapy Science
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• v.7 no.2
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• pp.439-457
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• 2000

The causes, risk factors and sequelae of mastectomy were studied, and the physical therapy approaches on post-mastectomy was discussed in this study. It was found that the patients taken mastectomy have experienced pins and needles in muscle, weakening of muscle, pains, deterioration of motion in joint region and activities of daily living, psychiatric sequelae, and etc even after the conservertive therapies like the chemical therapy, radiotherapy, immunotherapy, and hormone therapy. However, few study on the physical therapy approaches for patients with breast cancer has been carried in Korea at present. The followings were proposed as the physical therapy approaches. 1. Shoulder joint motion approach to relax the limit of range of motion 2. Control of breathing exercise for dealing with removal of the pectorailis muscle 3. Method to reduce the edema of arms for tackling the cut of lymph node 4. Method to reduce pains, pins and needles 5. Support home exercise program after discharging from hospital, sexual life and pregnancy, and activities of daily living training method.

• The Korean Journal of Applied Statistics
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• v.2 no.2
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• pp.27-35
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• 1989

This article deals with statistical inference on Interleukin-2 titer of which the clinical applications to cancer immunotherapy and some immunodeficiency diseases have been widely tried. A Linear model and the Bayesian approach are used to explain the bioassay which performs the measurements of IL-2 activity from an patient and an inference procedure including confidence intervals for the IL-2 titer of the patient through comparision with the Standard IL-2 is suggested and a real case of example is illustrated.

• Archives of Pharmacal Research
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• v.28 no.11
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• pp.1282-1286
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• 2005

The in vivo immunomodulatory function of the activity of murine natural killer (NK) cells induced by high mannuronic acid-containing alginate (HMA) was examined. HMA was injected i.p at doses of 25 and 100 mg/kg. The NK activity was 3 times higher with 100 mg/kg HMA than the baseline. In addition, in vitro studies of splenocytes cultured with HMA for 20 h showed a significant increase in NK activity at E:T ratio of 100: 1; a 160$\%$ and 210$\%$ increase at 10 and 100 $\mu$g/mL, respectively. There was a six fold increase in interferon-$\gamma$ production in a postculture of splenocytes with 100 $\mu$g/mL HMA. HMA had no suppressive effects on the lymphocyte function in the presence or absence of mitogens. This suggests that HMA is useful in cancer immunotherapy.