Anti‐tumor effects of mAb against <scp>l</scp>‐type amino acid transporter 1 (<scp>LAT</scp>1) bound to human and monkey <scp>LAT</scp>1 with dual avidity modes

Ueda, Satomi; Hayashi, Hidemi; Miyamoto, T.; Abe, Shinya; Hirai, Kana; Matsukura, Kanji; Yagi, Hideki; Hara, Yuta; Yoshida, Kinji; Okazaki, Shogo; Tamura, Masakazu; Abe, Yuki; Agatsuma, Toshinori; Niwa, Shin Ichiro; Masuko, Kazue; Masuko, Takashi

doi:10.1111/cas.13908

Cited by 23 publications

(30 citation statements)

References 48 publications

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“…Recently, Ueda et al tested whether targeting LAT1 by monoclonal anti-LAT1 antibodies might be a potential therapeutic approach. The authors found that the anti-LAT1 antibodies reduced proliferation of gastric and lung cancer cells in vitro and growth of colon cancer cells in vivo [81], suggesting that targeting LAT1 by monoclonal antibodies might be an alternative therapeutic option.…”

Section: Drug-mediated Inhibition Of Lat1mentioning

confidence: 99%

The L-Type Amino Acid Transporter LAT1—An Emerging Target in Cancer

Häfliger

Charles

2019

IJMS

151

117

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Chronic proliferation is a major hallmark of tumor cells. Rapidly proliferating cancer cells are highly dependent on nutrients in order to duplicate their cell mass during each cell division. In particular, essential amino acids are indispensable for proliferating cancer cells. Their uptake across the cell membrane is tightly controlled by membrane transporters. Among those, the L-type amino acid transporter LAT1 (SLC7A5) has been repeatedly found overexpressed in a vast variety of cancers. In this review, we summarize the most recent advances in our understanding of the role of LAT1 in cancer and highlight preclinical studies and drug developments underlying the potential of LAT1 as therapeutic target.

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Section: Drug-mediated Inhibition Of Lat1mentioning

confidence: 99%

The L-Type Amino Acid Transporter LAT1—An Emerging Target in Cancer

Häfliger

Charles

2019

IJMS

151

117

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“…We therefore, undertook the production of novel anti-HER3 mAbs. For the production of mAbs, in order to recognize the ECD of membrane proteins, we have so far utilized FCM to select mAbs reacting with transfectants expressing GFP-fused target molecules in a GFP-expression dependent manner as the first screening [27,28,41]. However, this method was difficult for rapid and simultaneous first screening of a large number of antibody samples.…”

Section: Discussionmentioning

confidence: 99%

“…We adopted rat but not mouse species for immunizing animals to develop therapeutic anti-HER3 mAbs, since the total number of B lymphocytes in rats is several times larger than those in mice and the capacity to generate the antibody diversity in rats is superior to mice [27], and rat mAbs could be routinely humanized for antibody therapy as we reported previously [28]. In this study, we have successfully developed novel functional rat mAbs recognizing ECD of HER3 expressed on the surface of various human epithelial cancers, and analyzed the therapeutic potential of these mAbs, in addition to the analysis concerning their germline segments and complementarity-determining region (CDR).…”

Section: Research Papermentioning

confidence: 99%

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Novel functional anti-HER3 monoclonal antibodies with potent anti-cancer effects on various human epithelial cancers

et al. 2020

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Copyright: Okita et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACTResistance of progressive cancers against chemotherapy is a serious clinical problem. In this context, human epidermal growth factor receptor 3 (HER3) can play important roles in drug resistance to HER1-and HER2-targeted therapies. Since clinical testing of anti-HER3 monoclonal antibodies (mAbs) such as patritumab could not show remarkable effect compared with existing drugs, we generated novel mAbs against anti-HER3. Novel rat mAbs reacted with HEK293 cells expressing HER3, but not with cells expressing HER1, HER2 or HER4. Specificity of mAbs was substantiated by the loss of mAb binding with knockdown by siRNA and knockout of CRISPR/ Cas9-based genome-editing. Analyses of CDR sequence and germline segment have revealed that seven mAbs are classified to four groups, and the binding of patritumab was inhibited by one of seven mAbs. Seven mAbs have shown reactivity with various human epithelial cancer cells, strong internalization activity of cell-surface HER3, and inhibition of NRG1 binding, NRG1-dependent HER3 phosphorylation and cell growth. Anti-HER3 mAbs were also reactive with in vivo tumor tissues and cancer tissue-originated spheroid. Ab4 inhibited in vivo tumor growth of human colon cancer cells in nude mice. Present mAbs may be superior to existing anti-HER3 mAbs and support existing anti-cancer therapeutic mAbs.

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“…The avidity of mAbs against CRC cells was evaluated according to our previous report 16 . Briefly, cells were reacted with a range of mAb concentrations (100 ng ~ 30 μg/mL), followed by the incubation with PE‐conjugated secondary pAb.…”

Section: Methodsmentioning

confidence: 99%

Antitumor effects of novel mAbs against cationic amino acid transporter 1 (CAT1) on human CRC with amplified CAT1 gene

et al. 2020

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Copy number alterations detected by comparative genomic hybridization (CGH) can lead to the identification of novel cancer‐related genes. We analyzed chromosomal aberrations in a set of 100 human primary colorectal cancers (CRCs) using CGH and found a solute carrier (SLC) 7A1 gene, which encodes cationic amino acid transporter 1 (CAT1) with 14 putative transmembrane domains, in a chromosome region (13q12.3) with a high frequency of gene amplifications. SLC7A1/CAT1 is a transporter responsible for the uptake of cationic amino acids (arginine, lysine, and ornithine) essential for cellular growth. Microarray and PCR analyses have revealed that mRNA transcribed from CAT1 is overexpressed in more than 70% of human CRC samples, and RNA interference–mediated knockdown of CAT1 inhibited the cell growth of CRCs. Rats were immunized with rat hepatoma cells expressing CAT1 tagged with green fluorescent protein (GFP), and rat splenocytes were fused with mouse myeloma cells. Five rat monoclonal antibodies (mAbs) (CA1 ~ CA5) reacting with HEK293 cells expressing CAT1‐GFP in a GFP expression–dependent manner were selected from established hybridoma clones. Novel anti‐CAT1 mAbs selectively reacted with human CRC tumor tissues compared with adjacent normal tissues according to immuno‐histochemical staining and bound strongly to numerous human cancer cell lines by flow cytometry. Anti‐CAT1 mAbs exhibited internalization activity, antibody‐dependent cellular cytotoxicity, and migration inhibition activity against CRC cell lines. Furthermore, CA2 inhibited the in vivo growth of human HT29 and SW‐C4 CRC tumors in nude mice. This study suggested CAT1 to be a promising target for mAb therapy against CRCs.

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Anti‐tumor effects of mAb against l‐type amino acid transporter 1 (LAT1) bound to human and monkey LAT1 with dual avidity modes

Cited by 23 publications

References 48 publications

The L-Type Amino Acid Transporter LAT1—An Emerging Target in Cancer

The L-Type Amino Acid Transporter LAT1—An Emerging Target in Cancer

Novel functional anti-HER3 monoclonal antibodies with potent anti-cancer effects on various human epithelial cancers

Antitumor effects of novel mAbs against cationic amino acid transporter 1 (CAT1) on human CRC with amplified CAT1 gene

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