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22 pages, 3890 KiB

Open AccessArticle

Rapid Evaluation of Antibody Fragment Endocytosis for Antibody Fragment–Drug Conjugates

by Eunhee G. Kim, Jieun Jeong, Junghyeon Lee, Hyeryeon Jung, Minho Kim, Yi Zhao, Eugene C. Yi and Kristine M. Kim

Biomolecules 2020, 10(6), 955; https://doi.org/10.3390/biom10060955 - 25 Jun 2020

Cited by 9 | Viewed by 5562

Abstract

Antibody–drug conjugates (ADCs) have emerged as the most promising strategy in targeted cancer treatment. Recent strategies for the optimization ADCs include the development of antibody fragment–drug conjugates (FDCs). The critical factor in the successful development of ADCs and FDCs is the identification of [...] Read more.

Antibody–drug conjugates (ADCs) have emerged as the most promising strategy in targeted cancer treatment. Recent strategies for the optimization ADCs include the development of antibody fragment–drug conjugates (FDCs). The critical factor in the successful development of ADCs and FDCs is the identification of tumor antigen-specific and internalizing antibodies (Abs). However, systematic comparison or correlation studies of internalization rates with different antibody formats have not been reported previously. In this study, we generated a panel of scFv-phage Abs using phage display technology and their corresponding scFv and scFv-Fc fragments and evaluated their relative internalization kinetics in relation to their antibody forms. We found that the relative rates and levels of internalization of scFv-phage antibodies positively correlate with their scFv and scFv-Fc forms. Our systematic study demonstrates that endocytosis of scFv-phage can serve as a predictive indicator for the assessment of Ab fragment internalization. Additionally, the present study demonstrates that endocytic antibodies can be rapidly screened and selected from phage antibody libraries prior to the conversion of phage antibodies for the generation of the conventional antibody format. Our strategic approach for the identification and evaluation of endocytic antibodies would expedite the selection for optimal antibodies and antibody fragments and be broadly applicable to ADC and FDC development. Full article

(This article belongs to the Special Issue Advances in Antibody Therapy of Cancer)

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12 pages, 2772 KiB

Open AccessArticle

Site-Specific Antibody–Drug Conjugates in Triple Variable Domain Fab Format

by Dobeen Hwang and Christoph Rader

Biomolecules 2020, 10(5), 764; https://doi.org/10.3390/biom10050764 - 14 May 2020

Cited by 12 | Viewed by 3492

Abstract

The interest in replacing the conventional immunoglobulin G (IgG) format of monoclonal antibodies (mAbs) and antibody–drug conjugates (ADCs) with alternative antibody and antibody-like scaffolds reflects a need to expand their therapeutic utility and potency while retaining their exquisite specificity, affinity, and low intrinsic [...] Read more.

The interest in replacing the conventional immunoglobulin G (IgG) format of monoclonal antibodies (mAbs) and antibody–drug conjugates (ADCs) with alternative antibody and antibody-like scaffolds reflects a need to expand their therapeutic utility and potency while retaining their exquisite specificity, affinity, and low intrinsic toxicity. For example, in the therapy of solid malignancies, the limited tumor tissue penetration and distribution of ADCs in IgG format mitigates a uniform distribution of the cytotoxic payload. Here, we report triple variable domain Fab (TVD–Fab) as a new format that affords the site-specific and stable generation of monovalent ADCs without the Fc domain and a drug-to-antibody ratio (DAR) of 2. TVD–Fabs harbor three variable fragment (Fv) domains: one for tumor targeting and two for the fast, efficient, precise, and stable conjugation of two cargos via uniquely reactive lysine residues. The biochemical and in vitro cytotoxicity properties of a HER2-targeting TVD–Fab before and after conjugation to a tubulin inhibitor were validated. In vivo, the TVD–Fab antibody carrier revealed a circulatory half-life of 13.3 ± 2.5 h and deeper tumor tissue distribution compared to our previously reported dual variable domain (DVD)–IgG1 format. Taken together, the TVD–Fab format merits further investigations as an antibody carrier of site-specific ADCs targeting solid malignancies. Full article

(This article belongs to the Special Issue Advances in Antibody Therapy of Cancer)

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12 pages, 1826 KiB

Open AccessArticle

A High-Throughput Single-Clone Phage Fluorescence Microwell Immunoassay and Laser-Driven Clonal Retrieval System

by Seohee Chang, Soohyun Kim, Jerome Han, Suji Ha, Hyunho Lee, Seo Woo Song, Daewon Lee, Sunghoon Kwon, Junho Chung and Junhoi Kim

Biomolecules 2020, 10(4), 517; https://doi.org/10.3390/biom10040517 - 29 Mar 2020

Cited by 5 | Viewed by 3566

Abstract

Phage display is one of the most frequently used platform technologies utilized to screen and select therapeutic antibodies, and has contributed to the development of more than 10 therapeutic antibodies used in the clinic. Despite advantages like efficiency and low cost, it has [...] Read more.

Phage display is one of the most frequently used platform technologies utilized to screen and select therapeutic antibodies, and has contributed to the development of more than 10 therapeutic antibodies used in the clinic. Despite advantages like efficiency and low cost, it has intrinsic technical limitations, such as the asymmetrical amplification of the library after each round of biopanning, which is regarded as a reason for it yielding a very limited number of antigen binders. In this study, we developed a high-throughput single-clonal screening system comprised of fluorescence immunoassays and a laser-driven clonal DNA retrieval system using microchip technology. Using this system, from a single-chain variable fragment (scFv) library displayed on phages with a complexity of 5.21 × 10⁵ harboring random mutations at five amino acid residues, more than 70,000 clones—corresponding to ~14% of the library complexity—were screened, resulting in 78 antigen-reactive scFv sequences with mutations restricted to the randomized residues. Our results demonstrate that this system can significantly reduce the number of biopanning rounds, or even eliminate the need for this process for libraries with lower complexity, providing an opportunity to obtain more diverse clones from the library. Full article

(This article belongs to the Special Issue Advances in Antibody Therapy of Cancer)

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15 pages, 3029 KiB

Open AccessCommunication

Machine Learning-Guided Prediction of Antigen-Reactive In Silico Clonotypes Based on Changes in Clonal Abundance through Bio-Panning

by Duck Kyun Yoo, Seung Ryul Lee, Yushin Jung, Haejun Han, Hwa Kyoung Lee, Jerome Han, Soohyun Kim, Jisu Chae, Taehoon Ryu and Junho Chung

Biomolecules 2020, 10(3), 421; https://doi.org/10.3390/biom10030421 - 8 Mar 2020

Cited by 7 | Viewed by 7835

Abstract

c-Met is a promising target in cancer therapy for its intrinsic oncogenic properties. However, there are currently no c-Met-specific inhibitors available in the clinic. Antibodies blocking the interaction with its only known ligand, hepatocyte growth factor, and/or inducing receptor internalization have been clinically [...] Read more.

c-Met is a promising target in cancer therapy for its intrinsic oncogenic properties. However, there are currently no c-Met-specific inhibitors available in the clinic. Antibodies blocking the interaction with its only known ligand, hepatocyte growth factor, and/or inducing receptor internalization have been clinically tested. To explore other therapeutic antibody mechanisms like Fc-mediated effector function, bispecific T cell engagement, and chimeric antigen T cell receptors, a diverse panel of antibodies is essential. We prepared a chicken immune scFv library, performed four rounds of bio-panning, obtained 641 clones using a high-throughput clonal retrieval system (TrueRepertoire^TM, TR), and found 149 antigen-reactive scFv clones. We also prepared phagemid DNA before the start of bio-panning (round 0) and, after each round of bio-panning (round 1–4), performed next-generation sequencing of these five sets of phagemid DNA, and identified 860,207 HCDR3 clonotypes and 443,292 LCDR3 clonotypes along with their clonal abundance data. We then established a TR data set consisting of antigen reactivity for scFv clones found in TR analysis and the clonal abundance of their HCDR3 and LCDR3 clonotypes in five sets of phagemid DNA. Using the TR data set, a random forest machine learning algorithm was trained to predict the binding properties of in silico HCDR3 and LCDR3 clonotypes. Subsequently, we synthesized 40 HCDR3 and 40 LCDR3 clonotypes predicted to be antigen reactive (AR) and constructed a phage-displayed scFv library called the AR library. In parallel, we also prepared an antigen non-reactive (NR) library using 10 HCDR3 and 10 LCDR3 clonotypes predicted to be NR. After a single round of bio-panning, we screened 96 randomly-selected phage clones from the AR library and found out 14 AR scFv clones consisting of 5 HCDR3 and 11 LCDR3 AR clonotypes. We also screened 96 randomly-selected phage clones from the NR library, but did not identify any AR clones. In summary, machine learning algorithms can provide a method for identifying AR antibodies, which allows for the characterization of diverse antibody libraries inaccessible by traditional methods. Full article

(This article belongs to the Special Issue Advances in Antibody Therapy of Cancer)

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21 pages, 3174 KiB

Open AccessArticle

Development of Human Monoclonal Antibody for Claudin-3 Overexpressing Carcinoma Targeting

by Hobin Yang, Hayeon Park, Yong Jin Lee, Jun Young Choi, TaeEun Kim, Nirmal Rajasekaran, Saehyung Lee, Kyoung Song, Sungyoul Hong, Joon-Seok Choi, Hyunbo Shim, Young-Deug Kim, Soohyun Hwang, Yoon-La Choi and Young Kee Shin

Biomolecules 2020, 10(1), 51; https://doi.org/10.3390/biom10010051 - 28 Dec 2019

Cited by 6 | Viewed by 8224

Abstract

Most malignant tumors originate from epithelial tissues in which tight junctions mediate cell–cell interactions. Tight junction proteins, especially claudin-3 (CLDN3), are overexpressed in various cancers. Claudin-3 is exposed externally during tumorigenesis making it a potential biomarker and therapeutic target. However, the development of [...] Read more.

Most malignant tumors originate from epithelial tissues in which tight junctions mediate cell–cell interactions. Tight junction proteins, especially claudin-3 (CLDN3), are overexpressed in various cancers. Claudin-3 is exposed externally during tumorigenesis making it a potential biomarker and therapeutic target. However, the development of antibodies against specific CLDN proteins is difficult, because CLDNs are four-transmembrane domain proteins with high homology among CLDN family members and species. Here, we developed a human IgG1 monoclonal antibody (h4G3) against CLDN3 through scFv phage display using CLDN3-overexpressing stable cells and CLDN3-embedded lipoparticles as antigens. The h4G3 recognized the native conformation of human and mouse CLDN3 without cross-reactivity to other CLDNs. The binding kinetics of h4G3 demonstrated a sub-nanomolar affinity for CLDN3 expressed on the cell surface. The h4G3 showed antibody-dependent cellular cytotoxicity (ADCC) according to CLDN3 expression levels in various cancer cells by the activation of FcγRIIIa (CD16a). The biodistribution of h4G3 was analyzed by intravenous injection of fluorescence-conjugated h4G3 which showed that it localized to the tumor site in xenograft mice bearing CLDN3-expressing tumors. These results indicate that h4G3 recognizes CLDN3 specifically, suggesting its value for cancer diagnosis, antibody-drug conjugates, and potentially as a chimeric antigen receptor (CAR) for CLDN3-expressing pan-carcinoma. Full article

(This article belongs to the Special Issue Advances in Antibody Therapy of Cancer)

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16 pages, 2488 KiB

Open AccessArticle

Trastuzumab Specific Epitope Evaluation as a Predictive and Prognostic Biomarker in Gastric Cancer Patients

by Jiwon Koh, Soo Kyung Nam, Youn Woo Lee, Jin Won Kim, Keun-Wook Lee, Chan-Young Ock, Do-Youn Oh, Sang-Hoon Ahn, Hyung-Ho Kim, Keon-Wook Kang, Woo Ho Kim, Ho-Young Lee and Hye Seung Lee

Biomolecules 2019, 9(12), 782; https://doi.org/10.3390/biom9120782 - 26 Nov 2019

Cited by 6 | Viewed by 5057

Abstract

While human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) antibodies bind to the intracellular domain, trastuzumab binds to the extracellular epitope of HER2 receptor: target of drug action. We aimed to evaluate clinical significance of the new IHC method assessing the target [...] Read more.

While human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) antibodies bind to the intracellular domain, trastuzumab binds to the extracellular epitope of HER2 receptor: target of drug action. We aimed to evaluate clinical significance of the new IHC method assessing the target of trastuzumab in gastric cancer (GC) patients and compare with conventional methods. Sixty-nine trastuzumab-treated GC patients were enrolled from two different cohorts. Additionally, we enrolled 528 consecutive GC patients to evaluate prognostic implications of HER2 test methods. HER2 status was assessed by trastuzumab IHC, HER2 IHC (4B5), and HER2 silver in situ hybridization (SISH). HER2 IHC showed 3+ in 48/69 trastuzumab-treated patients (69.6%), however, trastuzumab IHC showed 3+ in 25 (36.2%). Patients with trastuzumab IHC ≥2+ had significantly better progression-free survival (PFS) and overall survival (OS) than their counterpart (p = 0.014). In univariate analysis, trastuzumab IHC ≥2+ and HER2 IHC 3+ were only significant predictive factors for OS in trastuzumab-treated patients. Of the 528 consecutive GCs, patients with trastuzumab IHC ≥2+ had shorter disease-free survival (DFS) and OS (p = 0.008 and 0.031, respectively), while conventional methods failed to reveal any significant survival differences. HER2 assessment by trastuzumab IHC was different from conventional HER2 test results. Trastuzumab IHC was suggested to be a significant predictive factor for trastuzumab responsiveness and prognostic factor for consecutive GCs. Full article

(This article belongs to the Special Issue Advances in Antibody Therapy of Cancer)

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12 pages, 2625 KiB

Open AccessArticle

Antibody-Based Targeting of Cell Surface GRP94 Specifically Inhibits Cetuximab-Resistant Colorectal Cancer Growth

by Mee Hyun Jeoung, Taek-Keun Kim, Ji Woong Kim, Yea Bin Cho, Hee Jun Na, Byong Chul Yoo, Hyunbo Shim, Dong-Keun Song, Kyun Heo and Sukmook Lee

Biomolecules 2019, 9(11), 681; https://doi.org/10.3390/biom9110681 - 1 Nov 2019

Cited by 7 | Viewed by 4547

Abstract

Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. Cetuximab, a human/mouse chimeric monoclonal antibody, is effective in a limited number of CRC patients because of cetuximab resistance. This study aimed to identify novel therapeutic targets in cetuximab-resistant CRC [...] Read more.

Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. Cetuximab, a human/mouse chimeric monoclonal antibody, is effective in a limited number of CRC patients because of cetuximab resistance. This study aimed to identify novel therapeutic targets in cetuximab-resistant CRC in order to improve clinical outcomes. Through phage display technology, we isolated a fully human antibody strongly binding to the cetuximab-resistant HCT116 cell surface and identified the target antigen as glucose-regulated protein 94 (GRP94) using proteomic analysis. Short interfering RNA-mediated GRP94 knockdown showed that GRP94 plays a key role in HCT116 cell growth. In vitro functional studies revealed that the GRP94-blocking antibody we developed strongly inhibits the growth of various cetuximab-resistant CRC cell lines. We also demonstrated that GRP94 immunoglobulin G monotherapy significantly reduces HCT116 cell growth more potently compared to cetuximab, without severe toxicity in vivo. Therefore, cell surface GRP94 might be a potential novel therapeutic target in cetuximab-resistant CRC, and antibody-based targeting of GRP94 might be an effective strategy to suppress GRP94-expressing cetuximab-resistant CRC. Full article

(This article belongs to the Special Issue Advances in Antibody Therapy of Cancer)

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17 pages, 1794 KiB

Open AccessArticle

The HER2 S310F Mutant Can Form an Active Heterodimer with the EGFR, Which Can Be Inhibited by Cetuximab but Not by Trastuzumab as well as Pertuzumab

by Jung Won Shin, Soohyun Kim, Suji Ha, Byungsan Choi, Seongyeong Kim, Seock-Ah Im, Tae-Young Yoon and Junho Chung

Biomolecules 2019, 9(10), 629; https://doi.org/10.3390/biom9100629 - 19 Oct 2019

Cited by 10 | Viewed by 4973

Abstract

G309 or S310 mutations on the HER2 extracellular domain II induce receptor activation. Clinically, S310F is most frequent among HER2 extracellular domain mutations and patients with the S310F mutation without HER2 amplification responded to trastuzumab with or without the pertuzumab combination. However, the [...] Read more.

G309 or S310 mutations on the HER2 extracellular domain II induce receptor activation. Clinically, S310F is most frequent among HER2 extracellular domain mutations and patients with the S310F mutation without HER2 amplification responded to trastuzumab with or without the pertuzumab combination. However, the ability of S310F mutant to form homodimers or heterodimers with wild-type HER2 and other HER receptors, or their reactivity to trastuzumab and pertuzumab treatments, has not been reported. We overexpressed S310F as well as G309A, G309E and S310Y HER2 mutants and tested their reactivity to trastuzumab and pertuzumab. All mutants reacted to trastuzumab, but S310F mutant did not react to pertuzumab along with S310Y or G309E mutants. Thereafter, we tested the effects of trastuzumab and pertuzumab on 5637 cell line expressing both wild-type HER2 and S310F mutant. The ligand-independent HER2 homodimerization blocking antibody, trastuzumab, did not inhibit the activation of the HER2 receptor, suggesting that the S310F HER2 mutant did not form homodimers or heterodimers with wild-type HER2. Because 5637 cells overexpressed the EGFR, the effects of cetuximab and gefitinib were determined, and both inhibited the activation of HER2 and significantly reduced cell growth. Because pertuzumab did not inhibit the phosphorylation of HER2 while it bound to wild-type HER2, EGFR-mediated phosphorylation is expected to occur on the S310F mutant. To confirm whether the S310F mutant HER2 retained its affinity to the EGFR, single molecule interaction analyses using TIRF microscopy were performed, which showed that S310F mutant successfully formed complexes with EGFR. In conclusion, HER2 S310F mutant can form an active heterodimer with the EGFR and it can be inhibited by cetuximab, but not by trastuzumab in combination with pertuzumab. Full article

(This article belongs to the Special Issue Advances in Antibody Therapy of Cancer)

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Review

Jump to: Research

13 pages, 676 KiB

Open AccessReview

TSPAN8 as a Novel Emerging Therapeutic Target in Cancer for Monoclonal Antibody Therapy

by Kyun Heo and Sukmook Lee

Biomolecules 2020, 10(3), 388; https://doi.org/10.3390/biom10030388 - 3 Mar 2020

Cited by 23 | Viewed by 6302

Abstract

Tetraspanin 8 (TSPAN8) is a member of the tetraspanin superfamily that forms TSPAN8-mediated protein complexes by interacting with themselves and other various cellular signaling molecules. These protein complexes help build tetraspanin-enriched microdomains (TEMs) that efficiently mediate intracellular signal transduction. In physiological conditions, TSPAN8 [...] Read more.

Tetraspanin 8 (TSPAN8) is a member of the tetraspanin superfamily that forms TSPAN8-mediated protein complexes by interacting with themselves and other various cellular signaling molecules. These protein complexes help build tetraspanin-enriched microdomains (TEMs) that efficiently mediate intracellular signal transduction. In physiological conditions, TSPAN8 plays a vital role in the regulation of biological functions, including leukocyte trafficking, angiogenesis and wound repair. Recently, reports have increasingly shown the functional role and clinical relevance of TSPAN8 overexpression in the progression and metastasis of several cancers. In this review, we will highlight the physiological and pathophysiological roles of TSPAN8 in normal and cancer cells. Additionally, we will cover the current status of monoclonal antibodies specifically targeting TSPAN8 and the importance of TSPAN8 as an emerging therapeutic target in cancers for monoclonal antibody therapy. Full article

(This article belongs to the Special Issue Advances in Antibody Therapy of Cancer)

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14 pages, 1526 KiB

Open AccessReview

Reprogramming the Constant Region of Immunoglobulin G Subclasses for Enhanced Therapeutic Potency against Cancer

by Tae Hyun Kang and Sang Taek Jung

Biomolecules 2020, 10(3), 382; https://doi.org/10.3390/biom10030382 - 1 Mar 2020

Cited by 7 | Viewed by 4098

Abstract

The constant region of immunoglobulin (Ig) G antibodies is responsible for their effector immune mechanism and prolongs serum half-life, while the fragment variable (Fv) region is responsible for cellular or tissue targeting. Therefore, antibody engineering for cancer therapeutics focuses on both functional efficacy [...] Read more.

The constant region of immunoglobulin (Ig) G antibodies is responsible for their effector immune mechanism and prolongs serum half-life, while the fragment variable (Fv) region is responsible for cellular or tissue targeting. Therefore, antibody engineering for cancer therapeutics focuses on both functional efficacy of the constant region and tissue- or cell-specificity of the Fv region. In the functional aspect of therapeutic purposes, antibody engineers in both academia and industry have capitalized on the constant region of different IgG subclasses and engineered the constant region to enhance therapeutic efficacy against cancer, leading to a number of successes for cancer patients in clinical settings. In this article, we review IgG subclasses for cancer therapeutics, including (i) IgG1, (ii) IgG2, 3, and 4, (iii) recent findings on Fc receptor functions, and (iv) future directions of reprogramming the constant region of IgG to maximize the efficacy of antibody drug molecules in cancer patients. Full article

(This article belongs to the Special Issue Advances in Antibody Therapy of Cancer)

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31 pages, 2097 KiB

Open AccessReview

Bispecific Antibodies and Antibody–Drug Conjugates for Cancer Therapy: Technological Considerations

by Hyunbo Shim

Biomolecules 2020, 10(3), 360; https://doi.org/10.3390/biom10030360 - 26 Feb 2020

Cited by 82 | Viewed by 16039

Abstract

The ability of monoclonal antibodies to specifically bind a target antigen and neutralize or stimulate its activity is the basis for the rapid growth and development of the therapeutic antibody field. In recent years, traditional immunoglobulin antibodies have been further engineered for better [...] Read more.

The ability of monoclonal antibodies to specifically bind a target antigen and neutralize or stimulate its activity is the basis for the rapid growth and development of the therapeutic antibody field. In recent years, traditional immunoglobulin antibodies have been further engineered for better efficacy and safety, and technological developments in the field enabled the design and production of engineered antibodies capable of mediating therapeutic functions hitherto unattainable by conventional antibody formats. Representative of this newer generation of therapeutic antibody formats are bispecific antibodies and antibody–drug conjugates, each with several approved drugs and dozens more in the clinical development phase. In this review, the technological principles and challenges of bispecific antibodies and antibody–drug conjugates are discussed, with emphasis on clinically validated formats but also including recent developments in the fields, many of which are expected to significantly augment the current therapeutic arsenal against cancer and other diseases with unmet medical needs. Full article

(This article belongs to the Special Issue Advances in Antibody Therapy of Cancer)

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15 pages, 1351 KiB

Open AccessEditor’s ChoiceReview

Recent Advances in Allogeneic CAR-T Cells

by Dong Wook Kim and Je-Yoel Cho

Biomolecules 2020, 10(2), 263; https://doi.org/10.3390/biom10020263 - 10 Feb 2020

Cited by 73 | Viewed by 10834

Abstract

In recent decades, great advances have been made in the field of tumor treatment. Especially, cell-based therapy targeting tumor associated antigen (TAA) has developed tremendously. T cells were engineered to have the ability to attack tumor cells by generating CAR constructs consisting of [...] Read more.

In recent decades, great advances have been made in the field of tumor treatment. Especially, cell-based therapy targeting tumor associated antigen (TAA) has developed tremendously. T cells were engineered to have the ability to attack tumor cells by generating CAR constructs consisting of genes encoding scFv, a co-stimulatory domain (CD28 or TNFRSF9), and CD247 signaling domains for T cell proliferation and activation. Principally, CAR-T cells are activated by recognizing TAA by scFv on the T cell surface, and then signaling domains inside cells connected by scFv are subsequently activated to induce downstream signaling pathways involving T cell proliferation, activation, and production of cytokines. Many efforts have been made to increase the efficacy and persistence and also to decrease T cell exhaustion. Overall, allogeneic and universal CAR-T generation has attracted much attention because of their wide and prompt usage for patients. In this review, we summarized the current techniques for generation of allogeneic and universal CAR-T cells along with their disadvantages and limitations that still need to be overcome. Full article

(This article belongs to the Special Issue Advances in Antibody Therapy of Cancer)

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