In Silico Design of Peptide Inhibitors Targeting HER2 for Lung Cancer Therapy DOI Open Access
Heba Alkhatabi,

Hisham N. Alatyb

Cancers, Journal Year: 2024, Volume and Issue: 16(23), P. 3979 - 3979

Published: Nov. 27, 2024

Background/Objectives: Human epidermal growth factor receptor 2 (HER2) is overexpressed in several malignancies, such as breast, gastric, ovarian, and lung cancers, where it promotes aggressive tumor proliferation unfavorable prognosis. Targeting HER2 has thus emerged a crucial therapeutic strategy, particularly for HER2-positive malignancies. The present study focusses on the design optimization of peptide inhibitors targeting HER2, utilizing machine learning to identify enhance candidates with elevated binding affinities. aim provide novel options malignancies linked overexpression. Methods: This started extraction structural examination protein, succeeded by designing sequences derived from essential interaction residues. A technique (XGBRegressor model) was employed predict affinities, identifying top 20 possibilities. underwent further screening via FreeSASA methodology free energy calculations, resulting selection four primary (pep-17, pep-7, pep-2, pep-15). Density functional theory (DFT) calculations were utilized evaluate molecular reactivity characteristics, while dynamics simulations performed investigate inhibitory mechanisms selectivity effects. Advanced computational methods, QM/MM simulations, offered more understanding peptide–protein interactions. Results: Among principal peptides, pep-7 exhibited most DFT values (−3386.93 kcal/mol) maximum dipole moment (10,761.58 Debye), whereas pep-17 had lowest value (−5788.49 minimal (2654.25 Debye). Molecular indicated that steady −12.88 kcal/mol consistently bound inside pocket during 300 ns simulation. showed overall total system, which combines both QM MM contributions, remained around −79,000 ± 400 kcal/mol, suggesting entire protein–peptide complex stable state, maintaining strong, well-integrated binding. Conclusions: Pep-7 promising peptide, displaying strong stability, favorable energy, stability HER2-overexpressing cancer models. These findings suggest viable candidate offering potential treatment strategy against HER2-driven

Language: Английский

Antitumor activities of anti‑CD44 monoclonal antibodies in mouse xenograft models of esophageal cancer DOI Creative Commons

Kenichiro Ishikawa,

Hiroyuki Suzuki, Tomokazu Ohishi

et al.

Oncology Reports, Journal Year: 2024, Volume and Issue: 52(5)

Published: Aug. 29, 2024

CD44 is a type I transmembrane glycoprotein associated with poor prognosis in various solid tumors. Since plays critical role tumor development by regulating cell adhesion, survival, proliferation and stemness, it has been considered target for therapy. Anti‑CD44 monoclonal antibodies (mAbs) have developed applied to antibody‑drug conjugates chimeric antigen receptor‑T Anti-pan‑CD44 mAbs, C44Mab‑5 C44Mab‑46, which recognize both standard (CD44s) variant isoforms were previously developed. The present study generated mouse IgG2a version of the anti‑pan‑CD44 mAbs (5‑mG2a C44Mab‑46‑mG2a) evaluate antitumor activities against CD44‑positive cells. Both 5‑mG2a C44Mab‑46‑mG2a recognized CD44s‑overexpressed CHO‑K1 (CHO/CD44s) cells esophageal line (KYSE770) flow cytometry. Furthermore, could activate effector presence CHO/CD44s exhibited complement-dependent cytotoxicity KYSE770 administration significantly suppressed xenograft compared control IgG2a. These results indicate that exert cancers be promising therapeutic regimen

Language: Английский

Citations

6
Antitumor Activities of a Humanized Cancer-Specific Anti-HER2 Monoclonal Antibody, humH2Mab-250 in Human Breast Cancer Xenografts DOI Open Access
Mika K. Kaneko, Hiroyuki Suzuki, Tomokazu Ohishi

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 1079 - 1079

Published: Jan. 26, 2025

Monoclonal antibody (mAb) and cell-based immunotherapies represent cutting-edge strategies for cancer treatment. However, safety concerns persist due to the potential targeting of normal cells that express reactive antigens. Therefore, it is crucial develop cancer-specific mAbs (CasMabs) can bind antigens exhibit antitumor activity in vivo, thereby reducing risk adverse effects. We previously screened human epidermal growth factor receptor 2 (HER2) successfully developed a anti-HER2 mAb, H2Mab-250/H2CasMab-2 (mouse IgG1, kappa). In this study, we assessed both vitro vivo efficacy humanized H2Mab-250 (humH2Mab-250). Although humH2Mab-250 showed lower reactivity HER2-overexpressed Chinese hamster ovary-K1 (CHO/HER2) breast cell lines (BT-474 SK-BR-3) than trastuzumab flow cytometry, similar antibody-dependent cellular cytotoxicity (ADCC) against CHO/HER2 presence effector splenocytes. addition, exhibited significant complement-dependent (CDC) compared trastuzumab. Furthermore, possesses compatible effects xenografts with These findings highlight distinct roles ADCC CDC suggest direction clinical development HER2-positive tumors.

Language: Английский

Citations

0
Development of a novel anti-erythropoietin-producing hepatocellular receptor B6 monoclonal antibody Eb6Mab-3 for flow cytometry DOI Creative Commons
Tomohiro Tanaka, Yu Kaneko, Hirotaka Yamamoto

et al.

Biochemistry and Biophysics Reports, Journal Year: 2025, Volume and Issue: 41, P. 101960 - 101960

Published: Feb. 21, 2025

Language: Английский

Citations

0
Immunological analysis of LC16m8 vaccine: preclinical and early clinical insights into mpox DOI
Kouji Kobiyama, Daichi Utsumi,

Yu Kaku

et al.

EBioMedicine, Journal Year: 2025, Volume and Issue: 115, P. 105703 - 105703

Published: April 15, 2025

Language: Английский

Citations

0
Anti-HER2 cancer-specific mAb, H2Mab-250-hG<sub>1</sub> possesses higher complement-dependent cytotoxicity than trastuzumab DOI Open Access
Hiroyuki Suzuki, Tomokazu Ohishi, Tomohiro Tanaka

et al.

Published: July 11, 2024

Cancer-specific monoclonal antibodies (CasMabs) that recognize cancer-specific antigens with in vivo antitumor efficacy are innovative therapeutic strategies for minimizing the adverse effects. We previously established a anti-human epidermal growth factor receptor 2 (HER2)monoclonal antibody (mAb), H2Mab-250/H2CasMab-2. In flow cytometry and immunohistochemistry, H2Mab-250 reacted HER2-positive breast cancer cells but did not show reactivity to normal epithelial cells. contrast, clinically approved anti-HER2 mAb, trastuzumab, strongly recognizes both cytometry. The human IgG1 version of (H2Mab-250-hG1) possesses compatible effects against xenografts trastuzumab despite lower affinity effector activation than vitro. This study compared antibody-dependent cellular cytotoxicity (ADCC) complement-dependent (CDC) between H2Mab-250-hG1 trastuzumab. Both showed ADCC activity CHO/HER2 cell lines (BT-474 SK-BR-3) presence natural killer Some tendency was observed more significant effect H2Mab-250-hG1. Importantly, exhibited superior CDC these Similar results were obtained mouse IgG2a types These suggest different contributions activities indicate future direction clinical development tumors.

Language: Английский

Citations

3
Anti-HER2 Cancer-Specific mAb, H2Mab-250-hG1, Possesses Higher Complement-Dependent Cytotoxicity than Trastuzumab DOI Open Access
Hiroyuki Suzuki, Tomokazu Ohishi, Tomohiro Tanaka

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(15), P. 8386 - 8386

Published: Aug. 1, 2024

Cancer-specific monoclonal antibodies (CasMabs) that recognize cancer-specific antigens with in vivo antitumor efficacy are innovative therapeutic strategies for minimizing adverse effects. We previously established a anti-human epidermal growth factor receptor 2 (HER2) antibody (mAb), H2Mab-250/H2CasMab-2. In flow cytometry and immunohistochemistry, H2Mab-250 reacted HER2-positive breast cancer cells but did not show reactivity to normal epithelial cells. contrast, clinically approved anti-HER2 mAb, trastuzumab, strongly recognizes both cytometry. The human IgG1 version of (H2Mab-250-hG1) possesses compatible effects against xenografts trastuzumab despite the lower affinity effector activation than vitro. This study compared antibody-dependent cellular cytotoxicity (ADCC) complement-dependent (CDC) between H2Mab-250-hG1 trastuzumab. Both showed ADCC activity HER2-overexpressed Chinese hamster ovary -K1 cell lines (BT-474 SK-BR-3) presence natural killer Some tendency was observed where more significant effect H2Mab-250-hG1. Importantly, exhibited superior CDC these Similar results were obtained mouse IgG2a types These suggest different contributions activities indicate future direction clinical development tumors.

Language: Английский

Citations

3
Anti-CD44 Variant 10 Monoclonal Antibody Exerts Antitumor Activity in Mouse Xenograft Models of Oral Squamous Cell Carcinomas DOI Open Access

Kenichiro Ishikawa,

Hiroyuki Suzuki, Tomokazu Ohishi

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(17), P. 9190 - 9190

Published: Aug. 24, 2024

CD44 regulates cell adhesion, proliferation, survival, and stemness has been considered a tumor therapy target. possesses the shortest standard (CD44s) variety of variant (CD44v) isoforms. Since expression CD44v is restricted in epithelial cells carcinomas compared to CD44s, promising target for monoclonal antibody (mAb) therapy. We previously developed an anti-CD44v10 mAb, C

Language: Английский

Citations

3
Antitumor activities against breast cancers by an afucosylated anti‐HER2 monoclonal antibody H2Mab‐77‐mG2a‐f DOI Creative Commons
Tomohiro Tanaka, Hiroyuki Suzuki, Tomokazu Ohishi

et al.

Cancer Science, Journal Year: 2023, Volume and Issue: 115(1), P. 298 - 309

Published: Nov. 9, 2023

Abstract Breast cancer patients with high levels of human epidermal growth factor receptor 2 (HER2) expression have worse clinical outcomes. Anti‐HER2 monoclonal antibody (mAb) is the most important therapeutic modality for HER2‐positive breast cancer. We previously immunized mice ectodomain HER2 to create anti‐HER2 mAb, H Mab‐77 (mouse IgG 1 , kappa). This was then altered produce Mab‐77‐mG 2a ‐f, an afucosylated mouse . In present work, we examined reactivity ‐f and antitumor effects against cancers in vitro vivo. BT‐474, endogenously HER2‐expressing cell line, identified by a strong binding affinity (a dissociation constant [ K D ]: 5.0 × 10 −9 M). could stain tissues immunohistochemistry detect protein Western blot analysis. Furthermore, demonstrated antibody‐dependent cellular cytotoxicity (ADCC) complement‐dependent (CDC) BT‐474 cells. MDA‐MB‐468, HER2‐negative unaffected ‐f. Additionally, BT‐474‐bearing tumor xenograft model, substantially suppressed development when compared control mAb. contrast, MDA‐MB‐468‐bearing model showed no response These findings point possibility as treatment regimen showing that it has on tumors.

Language: Английский

Citations

7
Defucosylated Monoclonal Antibody (H2Mab-139-mG2a-f) Exerted Antitumor Activities in Mouse Xenograft Models of Breast Cancers against Human Epidermal Growth Factor Receptor 2 DOI Creative Commons
Hiroyuki Suzuki, Tomokazu Ohishi, Ren Nanamiya

et al.

Current Issues in Molecular Biology, Journal Year: 2023, Volume and Issue: 45(10), P. 7734 - 7748

Published: Sept. 23, 2023

The clinically approved human epidermal growth factor receptor 2 (HER2)-targeting monoclonal antibodies (mAbs), trastuzumab, and pertuzumab, target domains IV II, respectively. Trastuzumab is now the standard treatment for HER2-overexpressed breast gastric cancers, trastuzumab in combination with pertuzumab showed clinical benefit. However, there still exist patients who do not respond to therapy. Furthermore, HER2 mutants that cannot be recognized by were found tumors. Therefore, novel anti-HER2 mAbs modalities have been desired. In our previous study, we developed a domain I mAb, H

Language: Английский

Citations

5
Establishment of a Highly-sensitive Anti-EphB2 Monoclonal Antibody Eb2Mab-3 for Flow Cytometry DOI Open Access

Rena Ubukata,

Hiroyuki Suzuki,

Miu Hirose

et al.

Published: June 11, 2024

EphB2 is a member of the Eph family tyrosine kinase receptors. binds to ephrin-B1, ephrin-B2, and ephrin-B3, which are critical regulators vascular nervous development through controlling cell migration axon guidance. overexpressed in tumors, including glioma, breast cancer, hepatocellular carcinoma, malignant mesothelioma, it functions as tumor promoter. Therefore, monoclonal antibodies (mAbs) against essential for diagnosis therapy EphB2-positive tumors. In this study, we developed novel mAbs human using Cell-Based Immunization Screening (CBIS) method. One established anti-EphB2 mAbs, Eb2Mab-3 (mouse IgG1, kappa), reacted with EphB2-overexpressed Chinese hamster ovary-K1 (CHO/EphB2) an endogenously EphB2-expressing cancer line (LS174T) by flow cytometry. Using cytometry, dissociation constant (KD) values CHO/EphB2 LS174T were determined 1.1 × 10−9 M 3.6 10−10 M, respectively. These results indicated that possesses high affinity detecting could apply therapy.

Language: Английский

Citations

1