Reviews : Invited Review ; Strategies and Advancement in Antibody-Drug Conjugate Optimization for Targeted Cancer Therapeutics

( Eunhee G Kim ),( Kristine M Kim ) 한국응용약물학회 2015 Biomolecules & Therapeutics(구 응용약물학회지) Vol.23 No.6

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® (anti-CD30-drug conjugate) and Kadcyla® (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.

Strategies and Advancement in Antibody-Drug Conjugate Optimization for Targeted Cancer Therapeutics

Kim, Eunhee G.,Kim, Kristine M. The Korean Society of Applied Pharmacology 2015 Biomolecules & Therapeutics(구 응용약물학회지) Vol.23 No.6

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.

A comparative study on antibody immobilization strategies onto solid surface

이지은,서정현,김창섭,권윤경,하정협,최석순,차형준 한국화학공학회 2013 Korean Journal of Chemical Engineering Vol.30 No.10

Antibody immobilization onto solid surface has been studied extensively for a number of applications including immunoassays, biosensors, and affinity chromatography. For most applications, a critical consideration regarding immobilization of antibody is orientation of its antigen-binding site with respect to the surface. We compared two oriented antibody immobilization strategies which utilize thiolated-protein A/G and thiolated-secondary antibody as linker molecules with the case of direct surface immobilization of thiol-conjugated target antibody. Antibody immobilization degree and surface topography were evaluated by surface plasmon resonance and atomic force microscope, respectively. Protein A/G-mediated immobilization strategy showed the best result and secondary antibody-mediated immobilization was the worst for the total immobilization levels of target antibodies. However, when considering realto-ideal ratio for antigen binding, total target antigen binding levels (oriented target antibody immobilization levels)had the following order: secondary antibody-mediated immobilization>protein A/G-mediated immobilization>direct thiol-conjugated immobilization. Thus, we confirmed that protein A/G- and secondary antibody-mediated strategies,which consider orientation of target antibody immobilization, showed significantly high antigen binding efficiencies compared to direct random immobilization method. Collectively, the oriented antibody immobilization methods using linker materials could be useful in diverse antibody-antigen interaction-involved application fields.

류마티 질환에서 항 Cardiolipin 항체의 출현 빈도와 임상적 의의

송영욱,계경채,박선양,최강원 대한내과학회 1990 대한내과학회지 Vol.38 No.5

We analyzed the frequency and clinical significance of serum anticardiolipin antibodies by enzyme linked immunosorbent assay in 67 patients with various rheumatic diseases. A significantly elevated frequency of anticardiolipin antibody was found in patients with systemic lupus erythematosus(44%), rheumatoid arthritis(39%) and dermatomyositis(20%). None of the patients with progressive systemic sclerosis had anticardiolipin antibody. In the case of SLE, the anticardiolipin antibody level seemed to parallel the disease activity. Along with clinical improvement, the anticardiolipin antibody and anti-ds DNA antibody level decreased, while the serum complement increased. The presence of anticardiolipin antibody correlated with elevated ESR and positive Coombs' test in patients with systemic lupus erythematosus. These results suggest that the anticardiolipin antibody levels reflect disease activity and that some anticardiolipin antibody may be capable of recognizing a phospholipid epitope on the surface of the red blood cell. No significant association was found between the anticardiolipin antibody and the rheumatoid factor or the antinuclear antibody in patients with rheumatoid arthritis. There was no significant association between the anticardiolipin antibody and skin rash, Raynaud's phenomenon, antinuclear antibody or the rheumatoid factor in patients with dermatomyositis.

RD-05, a novel anti-CD154 antibody, efficiently inhibits generation of anti-drug antibody without the risk of thrombus formation in non-human primates

Lee, Jae-Il,Choi, Yun-Jung,Park, Hi-Jung,Jung, Kyeong Cheon,Park, Seong Hoe Elsevier 2018 Biochemical and biophysical research communication Vol.498 No.4

<P><B>Abstract</B></P> <P>Antibody formation against therapeutic agents, such as tumor necrosis factor inhibitors and Factor VIII, that leads to treatment failure has become a major challenge in the treatment of rheumatoid arthritis and hemophilia. It is well known that anti-CD154 antibodies have the highest potential to inhibit these types of adverse immune responses. Nevertheless, the formation of thromboemboli is the major hurdle in the clinical application of these anti-CD154 blocking antibodies. For this, we attempted to derive an idea as to how this major complication can be eliminated. Consequently, we developed a novel anti-CD154 chimeric antibody, which was made by genetic modification of a portion of human IgG4 Fc. This antibody has an almost comparable antigen binding affinity to a previously developed 5C8 clone and near completely inhibited CD40-CD154 interaction and T cell-dependent B cell activation <I>in vitro</I>. Even under the condition, where we injected immune complexes comprised of RD-05 and CD154 antigen, the formation of thromboembolism was not seen in human FcγRIIA-transgenic mice, whereas the converse was exactly true in the case of 5C8 antibody. Notably, just two injections of RD-05 antibody was sufficient to inhibit the antibody formation against adalimumab during 3–4 months in cynomolgus macaques, in which adalimumab was repeatedly injected for 12 weeks. Based on these findings, we suggest that this RD-05 antibody can be applied to antibody-mediated autoimmune diseases, including systemic lupus erythematosus and immune thrombocytopenic purpura.</P> <P><B>Highlights</B></P> <P> <UL> <LI> RD-05 is an anti-CD154 antibody with reduced binding affinity to Fcγ receptors. </LI> <LI> RD-05 did not elicit the thrombosis, a major complication of anti-CD154 antibodies. </LI> <LI> RD-05 antibody sufficiently inhibited antibody response against adalimumab. </LI> </UL> </P>

A Novel Anti-PD-L1 Antibody Exhibits Antitumor Eff ects on Multiple Myeloma in Murine Models via Antibody-Dependent Cellular Cytotoxicity

( Jae-hee Ahn ),( Byung-hyun Lee ),( Seong-eun Kim ),( Bo-eun Kwon ),( Hyunjin Jeong ),( Jong Rip Choi ),( Min Jung Kim ),( Yong Park ),( Byung Soo Kim ),( Dae Hee Kim ),( Hyun-jeong Ko ) 한국응용약물학회 2021 Biomolecules & Therapeutics(구 응용약물학회지) Vol.29 No.2

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 myeloidderived 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-PDL1 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.

장티푸스 이환시 Salmonella typhi Vi 항원에 대한 IgG , IgM IgA 항체가의 시간에 따른 변화

김준명(June Myeong Kim),안광진(Kwang Jin Ahn),김응(Eung Kim),홍천수(Chein Soo Hong) 대한내과학회 1989 대한내과학회지 Vol.37 No.3

N/A The varied antigenicity of salmonella species is determined by O, H and Vi antigens whose chemical components and roles are recognized partiallty and are still under study. The Vi antigen of Salmonella typhi is known to have a specific role in the pathogenesis of typhoid fever by exerting a protective action upon the serum complement system and thus resisting phagocytosis. Lately, Vi antigen was introduced for the diagnosis of typhoid fever, and sequential changes of polyvalent immunoglobulin antibody titers against Vi antigen in typhoid fever were reported. So we studied immunological responses against Vi antigen in twelve patients with typhoid fever, and sequentially measured immunoglobulin G, M and A titers by indirect fluorescent antibody test using Vi antigen (Vi-IFAT). The IgG antibody titers were already increased 1 week after fever onset, reached a peak level at 3 to 4 weeks, and then showed some period of plateau followed by a gradual decrease after 2 to 3 months. The IgM antibody titers showed no definite increase in the early phase of the disease in most of the patients, but a slight increase was noted 2 to 3 weeks after fever onset followed by a rapid decrease thereafter. The IgA antibody titers were already highly increased 1 week after fever onset, and then showed some period of plateau followed by a rapid decrease after 6 to 8 weeks. Compared with previous studies regarding O antibody production in Korea, the pattern of antibody responses against Vi antigen was very similar. Based on these results, we found that IgG antibody production was predominant and IgM antibody production was relatively suppressed even in the acute phase of typhoid fever. Considering that Korea is one of the endemic areas of typhoid fever, a previously acquired immunity against typhoid fever or exhaustion of IgM antibody-forming cells may lead to the relatively low IgM antibody titers.

누드마우스에 이식된 인체대장암에서 I - 131 표지 항태아성암항원 단일클론항체를 이용한 방사면역치료법 : 치료성적에 관계되는 인자분석

김병태(Byung Tae Kim),고창순(Chang Soon Koh),이명철(Myung Chul Lee),정준기(June Key Chung),김상은(Sang Eun Kim),최용(Yong Choi),이경한(Kyung Han Lee),지대윤(Dae Yoon Chi),정홍근(Hong Keun Chung) 대한핵의학회 1995 핵의학 분자영상 Vol.29 No.3

N/A This study was designed to evaluate the effects of various factors on the therapeutic effect of the I-l3l labeled anti-carcinoembryonic antigen monoclonal antibody(anti-CEA antibody). Tetrazolium-based colorimetric assay (MTT) was used to compare in vitro cytotoxicity of 3 Korean colon cancer cell lines (SNU-C2A, SNU-C4, SNU-C5) for selection of proper 2 cell lines in this study. The changes of the size of tumor which was xenografted to nude mice (balb/c nu/nu) were compared in 4 groups (group treated I-131 labeled anti-CEA antibody, group treated with non-radiolabeled anti-CEA antibody, group treated with I-131. labeled anti-human chorionic gonadotropin monoclonal antibody (anti-hCG antibody) as nonspecific antibody, and group injected with normal saline as a control). Immunohistochemical staining and in vivo autoradiography were performed after excision of the xenografted tumor. The results were as below mentioned. The in vitro cytotoxic effect of I-131 labeled anti-CEA antibody is most prominent in SNU-C5 cell line between 3 cancer cell lines. The changes of xenografted tumor size in both SNU-C4 and SNU-C5 cell tumors at the thirteenth day after injection of the antibodies were smallest in the group treated with I-131 labeled anti-CEA antibody (SNU-C4/SNU-C5; 324/342%) comparing with other groups, group treated with anti-CEA antibody (622/660%), group treated with I-131 anti-hCG antibody (538/546%), and control group(1030/724%) (p〈0.02 in SNU-C4 and p〈0.1in SNU-C5 at the 13th day after injection of antibodies). On the thirteenth day after injection of the antibodies nude mice were sacreficed to count the radiouptake of tumor and to check the changes of tumor size. Correlations between radiouptake and change of tumor size were calculated in each groups and significant negative correlation was only obtained in the group treated with I-131 anti-CEA antibody (p〈0.05). There were no correlations between antigenic expression of carcinoembryonic antigen and distribution of anti-CEA antibody in both SNU-C4 and SNU-C5-cell tumors on immunoperoxidase staining Qn in vivo autoradiography the distributions of anti-CEA antibody were heterogeneous and the intensities of binding were various in SNU-C4 and SNU-C5 cell tumors. It is concluded that I-131 labeled tumor-specific monoclonal antibody, anti-CEA antibody is effective in suppressing the xenografted tumor growth and the effect is influenced by sensitivity of tumor cell itself to the radiolabeled antibody and other local factors instead of specificity of antibody.

The Highly Evolvable Antibody Fc Domain

Park, Hye In,Yoon, Hyun Woung,Jung, Sang Taek Elsevier 2016 Trends in biotechnology Vol.34 No.11

<P>The Fc region of the IgG antibody recruits immune leukocytes or serum complement molecules, which in turn triggers the clearance of defective cells such as tumor cells or infected cells. In addition, the Fc region is crucial for the prolonged serum persistence of circulating IgG antibodies through an intracellular trafficking and recycling mechanism. Recently, the utility of antibody Fc has been further expanded to include a new class of antigen-binding scaffolds. This review presents the recent progress in the field of antibody Fc engineering and highlights new biomolecular, cellular, and evolutionary approaches to overcome the limitations of conventional monoclonal therapeutic antibodies by engineering the antibody Fc domain.</P> <P><B>Trends</B></P> <P>To maximize the clinical benefits of immunotherapy, it is crucial to improve the efficacy and serum half-life of therapeutic antibodies.</P> <P>The IgG antibody Fc region is crucial in determining the therapeutic effector functions and prolonged serum half-life of IgG antibodies through its interaction with Fc-binding ligands such as FcγRs, C1q, and FcRn.</P> <P>Recent progress in understanding antibody Fc functions and the use of innovative high-throughput screening technologies have generated sets of engineered Fc antibody therapeutics with significantly improved effector functions, longer serum stability, and new antigen-binding capabilities.</P> <P>Using various biomolecular, cellular, and evolutionary approaches, additional IgG Fc variants evolved for a desired function will be developed and evaluated in the clinic in the near future.</P>

SARS-CoV-2 항체 검사의 임상적 유용성

김현수 대한임상미생물학회 2021 Annals of clinical microbiology Vol.24 No.3

SARS-CoV-2 antibody assay is a test that checks whether an antibody against the SARSCoV-2 virus has been formed in the blood after SARS-CoV-2 infection or vaccination. SARSCoV-2 antibody is detected 1–2 weeks after infection, and antibodies are produced inmore than 90% of infected patients. The duration for the formation of antibodies differs byindividual and by type of antibody. In the case of IgG, it is at least several months or longer,and the relationship between antibodies and immunity is being studied. As test methods,enzyme-linked immunosorbent assay (ELISA), chemiluminescence immunoassay (CIA),immunochromatographic assay, and neutralizing antibody assay have been developedand used. The target antibody to be detected differs depending on the type of recombinantantigen and the type of secondary antibody in reagents. Many kinds of commercializedSARS-CoV-2 antibody assays are currently being developed, and the S (spike) protein, N(nucleocapsid) protein, S1 or RBD (receptor binding domain) part of the S protein, and amixture of these antigens are used as recombinant antigens of reagents. IgG, IgM, IgA, or totalimmunoglobulin antibodies in patients’ blood that react with these reagent antigens aredetected. In this review, the types and performance of SARS-CoV-2 antibody tests and theguidelines for COVID-19 antibody tests published domestically and abroad were investigated.