• Biomolecules & Therapeutics
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• 제29권2호
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• pp.166-174
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• 2021

Multiple myeloma is a malignant cancer of plasma cells. Despite recent progress with immunomodulatory drugs and proteasome inhibitors, it remains an incurable disease that requires other strategies to overcome its recurrence and non-response. Based on the high expression levels of programmed death-ligand 1 (PD-L1) in human multiple myeloma isolated from bone marrow and the murine myeloma cell lines, NS-1 and MOPC-315, we propose PD-L1 molecule as a target of anti-multiple myeloma therapy. We developed a novel anti-PD-L1 antibody containing a murine immunoglobulin G subclass 2a (IgG2a) fragment crystallizable (Fc) domain that can induce antibody-dependent cellular cytotoxicity. The newly developed anti-PD-L1 antibody showed significant antitumor effects against multiple myeloma in mice subcutaneously, intraperitoneally, or intravenously inoculated with NS-1 and MOPC-315 cells. The anti-PD-L1 effects on multiple myeloma may be related to a decrease in the immunosuppressive myeloid-derived suppressor cells (MDSCs), but there were no changes in the splenic MDSCs after combined treatment with lenalidomide and the anti-PD-L1 antibody. Interestingly, the newly developed anti-PD-L1 antibody can induce antibody-dependent cellular cytotoxicity in the myeloma cells, which differs from the existing anti-PD-L1 antibodies. Collectively, we have developed a new anti-PD-L1 antibody that binds to mouse and human PD-L1 and demonstrated the antitumor effects of the antibody in several syngeneic murine myeloma models. Thus, PD-L1 is a promising target to treat multiple myeloma, and the novel anti-PD-L1 antibody may be an effective anti-myeloma drug via antibody-dependent cellular cytotoxicity effects.

• Biomolecules & Therapeutics
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• 제29권5호
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• pp.465-482
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• 2021

Lipids, which along with carbohydrates and proteins are among the most important nutrients for the living organism, have a variety of biological functions that can be applied widely in biomedicine. A fatty acid, the most fundamental biological lipid, may be classified by length of its aliphatic chain, and the short-, medium-, and long-chain fatty acids and each have distinct biological activities with therapeutic relevance. For example, short-chain fatty acids have immune regulatory activities and could be useful against autoimmune disease; medium-chain fatty acids generate ketogenic metabolites and may be used to control seizure; and some metabolites oxidized from long-chain fatty acids could be used to treat metabolic disorders. Glycerolipids play important roles in pathological environments, such as those of cancers or metabolic disorders, and thus are regarded as a potential therapeutic target. Phospholipids represent the main building unit of the plasma membrane of cells, and play key roles in cellular signaling. Due to their physical properties, glycerophospholipids are frequently used as pharmaceutical ingredients, in addition to being potential novel drug targets for treating disease. Sphingolipids, which comprise another component of the plasma membrane, have their own distinct biological functions and have been investigated in nanotechnological applications such as drug delivery systems. Saccharolipids, which are derived from bacteria, have endotoxin effects that stimulate the immune system. Chemically modified saccharolipids might be useful for cancer immunotherapy or as vaccine adjuvants. This review will address the important biological function of several key lipids and offer critical insights into their potential therapeutic applications.

• Biomolecules & Therapeutics
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• 제32권4호
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• pp.481-491
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• 2024

Paxlovid is the first approved oral treatment for coronavirus disease 2019 and includes nirmatrelvir, a protease inhibitor targeting the main protease (M^pro) of SARS-CoV-2, as one of the key components. While some specific mutations emerged in M^pro were revealed to significantly reduce viral susceptibility to nirmatrelvir in vitro, there is no report regarding resistance to nirmatrelvir in patients and animal models for SARS-CoV-2 infection yet. We recently developed xenograft tumors derived from Calu-3 cells in immunodeficient mice and demonstrated extended replication of SARS-CoV-2 in the tumors. In this study, we investigated the effect of nirmatrelvir administration on SARS-CoV-2 replication. Treatment with nirmatrelvir after virus infection significantly reduced the replication of the parental SARS-CoV-2 and SARS-CoV-2 Omicron at 5 days post-infection (dpi). However, the virus titers were completely recovered at the time points of 15 and 30 dpi. The virus genomes in the tumors at 30 dpi were analyzed to investigate whether nirmatrelvir-resistant mutant viruses had emerged during the extended replication of SARS-CoV-2. Various mutations in several genes including ORF1ab, ORF3a, ORF7a, ORF7b, ORF8, and N occurred in the SARS-CoV-2 genome; however, no mutations were induced in the M^pro sequence by a single round of nirmatrelvir treatment, and none were observed even after two rounds of treatment. The parental SARS-CoV-2 and its sublineage isolates showed similar IC₅₀ values of nirmatrelvir in Vero E6 cells. Therefore, it is probable that inducing viral resistance to nirmatrelvir in vivo is challenging differently from in vitro passage.

• Journal of Oral Medicine and Pain
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• 제30권3호
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• pp.301-317
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• 2005

전 세계적으로 구강암의 빈도는 점점 증가 추세이며, 특히 한국인의 있어 혀(tongue)는 구강암이 가장 호발하는 장소이다. 구강암은 발암 단계에서부터 과증식 병소(hyperplastic lesion), 이형성(dysplasia) 및 상피내암(carcinoma in situ) 을 거쳐 악성 암종으로 발전하는 다단계 발암과정을 보이며, 분자 생물학적 변이가 구강암을 진행시킴이 널리 알려져 있다. 또한, 구강암은 일반적으로 암세포의 증식 및 고사(apoptosis)의 억제가 중요한 역할을 하고 있다 알려져 있다. 그리고, Bcl-2 family 는 세포 고사에 주요한 역할을 하고 있음이 알려져 있다. 그러나, 이들과 관련한 구강암 발생과정의 변화에 대해서는 널리 연구된 바가 없다. 본 연구는 백서에서 발암 물질인 4-NQO로 구강암을 유도시키고, 구강암 발생 다단계별로 Bcl-2 family의 mRNA 변화를 RT-PCR을 이용해 살펴보았다. Bcl-2 family는 크게 3군, 즉 1) anti-apoptotic, 2) pro-apoptotic, 그리고 3) BH3 only protein으로 분류할 수 있으며, 본 연구에서 anti-apoptotic molecules인 Bcl-w는 모든 군에서 발현이 감소되었으며, Bcl-2는 발현이 증가 되었다. pro-apoptotic molecules에서는 Bad가 제 3군 (편평세포암종)에서 발현이 증가 되었고, 나머지는 감소하였다. BH-3 only protein에서는 Bmf가 제 2군에서, BBC3가 제 3군에서 발현이 증가하였고, 나머지는 모든 군에서 감소하였다. 결론적으로, 4-NQO로 유도된 백서의 발암단계에서, Bcl-2 family의 mRNA 양상은 다양하게 관찰되었으나, Bad 및 BBC3 mRNA가 제 3군에서, Bmf mRNA가 제 2군에서의 발현이 특별함을 알 수 있어, 다단계 발암과정에서의 구강암을 진단하는데 유용하리라 사료된다.