Improved Therapy of B-Cell Non-Hodgkin Lymphoma by Obinutuzumab-Dianthin Conjugates in Combination with the Endosomal Escape Enhancer SO1861

Overview

Journal Toxins (Basel)

Publisher MDPI

Specialty Toxicology

Date 2022 Jul 25

PMID 35878216

Authors

Hossein Panjideh

Nicole Niesler

Alexander Weng

Hendrik Fuchs

Affiliations

Soon will be listed here.

Abstract

Immunotoxins do not only bind to cancer-specific receptors to mediate the elimination of tumor cells through the innate immune system, but also increase target cytotoxicity by the intrinsic toxin activity. The plant glycoside SO1861 was previously reported to enhance the endolysosomal escape of antibody-toxin conjugates in non-hematopoietic cells, thus increasing their cytotoxicity manifold. Here we tested this technology for the first time in a lymphoma in vivo model. First, the therapeutic CD20 antibody obinutuzumab was chemically conjugated to the ribosome-inactivating protein dianthin. The cytotoxicity of obinutuzumab-dianthin (ObiDi) was evaluated on human B-lymphocyte Burkitt's lymphoma Raji cells and compared to human T-cell leukemia off-target Jurkat cells. When tested in combination with SO1861, the cytotoxicity for target cells was 131-fold greater than for off-target cells. In vivo imaging in a xenograft model of B-cell lymphoma in mice revealed that ObiDi/SO1861 efficiently prevents tumor growth (51.4% response rate) compared to the monotherapy with ObiDi (25.9%) and non-conjugated obinutuzumab (20.7%). The reduction of tumor volume and overall survival was also improved. Taken together, our results substantially contribute to the development of a combination therapy with SO1861 as a platform technology to enhance the efficacy of therapeutic antibody-toxin conjugates in lymphoma and leukemia.

Citing Articles

Synergistic Cytotoxicity of a Toxin Targeting the Epidermal Growth Factor Receptor and the Glycosylated Triterpenoid SO1861 in Prostate Cancer.

Fischer A, Masilamani A, Schultze-Seemann S, Wolf I, Gratzke C, Fuchs H J Cancer. 2023; 14(16):3039-3049.

PMID: 37859824 PMC: 10583583. DOI: 10.7150/jca.85691.

Enhanced cytotoxicity of a Exotoxin A based immunotoxin against prostate cancer by addition of the endosomal escape enhancer SO1861.

Masilamani A, Huber N, Nagl C, Dettmer-Monaco V, Monaco G, Wolf I Front Pharmacol. 2023; 14:1211824.

PMID: 37484018 PMC: 10358361. DOI: 10.3389/fphar.2023.1211824.

Saponin Fraction CIL1 from L. Enhances the Effect of a Targeted Toxin on Cancer Cells.

Koczurkiewicz-Adamczyk P, Grabowska K, Karnas E, Piska K, Wnuk D, Klas K Pharmaceutics. 2023; 15(5).

PMID: 37242592 PMC: 10221382. DOI: 10.3390/pharmaceutics15051350.

Correction: Panjideh et al. Improved Therapy of B-Cell Non-Hodgkin Lymphoma by Obinutuzumab-Dianthin Conjugates in Combination with the Endosomal Escape Enhancer SO1861. 2022, , 478.

Panjideh H, Niesler N, Weng A, Fuchs H Toxins (Basel). 2022; 14(10).

PMID: 36287991 PMC: 9608844. DOI: 10.3390/toxins14100703.

References

Amitai I, Gafter-Gvili A, Shargian-Alon L, Raanani P, Gurion R . Obinutuzumab-related adverse events: A systematic review and meta-analysis. Hematol Oncol. 2020; 39(2):215-221. DOI: 10.1002/hon.2828. View

Fuchs H, Weng A, Gilabert-Oriol R . Augmenting the Efficacy of Immunotoxins and Other Targeted Protein Toxins by Endosomal Escape Enhancers. Toxins (Basel). 2016; 8(7). PMC: 4963833. DOI: 10.3390/toxins8070200. View

Geden S, Gardner R, Fabbrini M, Ohashi M, Phanstiel Iv O, Teter K . Lipopolyamine treatment increases the efficacy of intoxication with saporin and an anticancer saporin conjugate. FEBS J. 2007; 274(18):4825-36. DOI: 10.1111/j.1742-4658.2007.06008.x. View

Khongorzul P, Ling C, Ullah Khan F, Ihsan A, Zhang J . Antibody-Drug Conjugates: A Comprehensive Review. Mol Cancer Res. 2019; 18(1):3-19. DOI: 10.1158/1541-7786.MCR-19-0582. View

Fabbrini M, Rappocciolo E, Carpani D, Solinas M, Valsasina B, Breme U . Characterization of a saporin isoform with lower ribosome-inhibiting activity. Biochem J. 1997; 322 ( Pt 3):719-27. PMC: 1218247. DOI: 10.1042/bj3220719. View

Bhargava C, Durkop H, Zhao X, Weng A, Melzig M, Fuchs H . Targeted dianthin is a powerful toxin to treat pancreatic carcinoma when applied in combination with the glycosylated triterpene SO1861. Mol Oncol. 2017; 11(11):1527-1543. PMC: 5664001. DOI: 10.1002/1878-0261.12115. View

Freeman C, Sehn L . A tale of two antibodies: obinutuzumab versus rituximab. Br J Haematol. 2018; 182(1):29-45. DOI: 10.1111/bjh.15232. View

Kutsch N, Pallasch C, Tausch E, Bohme V, Ritgen M, Liersch R . Efficacy and Safety of the Combination of Tirabrutinib and Entospletinib With or Without Obinutuzumab in Relapsed Chronic Lymphocytic Leukemia. Hemasphere. 2022; 6(4):e692. PMC: 8906452. DOI: 10.1097/HS9.0000000000000692. View

Bolognesi A, Polito L, Scicchitano V, Orrico C, Pasquinelli G, Musiani S . Endocytosis and intracellular localisation of type 1 ribosome-inactivating protein saporin-s6. J Biol Regul Homeost Agents. 2012; 26(1):97-109. View

10.

ONions J, Townsend W . The role of obinutuzumab in the management of follicular lymphoma. Future Oncol. 2019; 15(31):3565-3578. DOI: 10.2217/fon-2019-0193. View

11.

Weng A . A novel adenine-releasing assay for ribosome-inactivating proteins. J Chromatogr B Analyt Technol Biomed Life Sci. 2017; 1072:300-304. DOI: 10.1016/j.jchromb.2017.11.038. View

12.

Herter S, Herting F, Mundigl O, Waldhauer I, Weinzierl T, Fauti T . Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models. Mol Cancer Ther. 2013; 12(10):2031-42. DOI: 10.1158/1535-7163.MCT-12-1182. View

13.

Sefid F, Alagheband Bahrami A, Payandeh Z, Khalili S, Azamirad G, Kalantar S . Ofatumumab and Granzyme B as immunotoxin against CD20 antigen. In Silico Pharmacol. 2022; 10(1):6. PMC: 8933591. DOI: 10.1007/s40203-022-00120-6. View

14.

Sama S, Woith E, Walther W, Jerz G, Chen W, Hart S . Targeted suicide gene transfections reveal promising results in nu/nu mice with aggressive neuroblastoma. J Control Release. 2018; 275:208-216. DOI: 10.1016/j.jconrel.2018.02.031. View

15.

Zarinwall A, Asadian-Birjand M, Ag Seleci D, Maurer V, Trautner A, Garnweitner G . Magnetic Nanoparticle-Based Dianthin Targeting for Controlled Drug Release Using the Endosomal Escape Enhancer SO1861. Nanomaterials (Basel). 2021; 11(4). PMC: 8074366. DOI: 10.3390/nano11041057. View

16.

Tobinai K, Klein C, Oya N, Fingerle-Rowson G . A Review of Obinutuzumab (GA101), a Novel Type II Anti-CD20 Monoclonal Antibody, for the Treatment of Patients with B-Cell Malignancies. Adv Ther. 2016; 34(2):324-356. PMC: 5331088. DOI: 10.1007/s12325-016-0451-1. View

17.

Hess G, Huttmann A, Witzens-Harig M, Dreyling M, Keller U, Marks R . A phase II trial to evaluate the combination of pixantrone and obinutuzumab for patients with relapsed aggressive lymphoma: Final results of the prospective, multicentre GOAL trial. Br J Haematol. 2022; 198(3):482-491. DOI: 10.1111/bjh.18161. View

18.

Allen T . Ligand-targeted therapeutics in anticancer therapy. Nat Rev Cancer. 2002; 2(10):750-63. DOI: 10.1038/nrc903. View

19.

Hertler A, Frankel A . Immunotoxins: a clinical review of their use in the treatment of malignancies. J Clin Oncol. 1989; 7(12):1932-42. DOI: 10.1200/JCO.1989.7.12.1932. View

20.

Gilabert-Oriol R, Thakur M, von Mallinckrodt B, Hug T, Wiesner B, Eichhorst J . Modified trastuzumab and cetuximab mediate efficient toxin delivery while retaining antibody-dependent cell-mediated cytotoxicity in target cells. Mol Pharm. 2013; 10(11):4347-57. DOI: 10.1021/mp400444q. View