Background and purpose:The lack of a new effective treatment for small cell lung cancer (SCLC) is an unresolved problem. Due to the new identification of delta-like ligand 3 (DLL3) and its high expression in SCLC patients, the use of DLL3 in target therapy can be effective. The use of bacterial toxins belonging to the ADP-ribosyl transferase toxins family and human enzymes to remove cancerous cells has been effective in the structure of immunotoxins. In this study, single-chain fragment variable of rovalpituzumab antibody fused to granzyme B (Rova-GrB) and PltA of typhoid toxin (Rova-Typh) as immunotoxins were designed, and bioinformatics analysis was done.Experimental approach:In silico analysis including the physicochemical properties, evaluation of the secondary and tertiary structure, refinement and validation of 3D models, and docking were performed. Immunotoxin genes were cloned and expressed in the Escherichia coli BL21 (DE3) host, purified, subsequently confirmed by western blotting and their secondary structure was evaluated by the circular dichroism method.Findings/Results:The bioinformatics analysis showed that Rova-GrB and Rova-Typh had hydrophilic properties, their codon optimization parameters were standard, validation parameters were improved after immunotoxin refinement, and docking analysis showed that the binding domain of immunotoxins could bind the N-terminal region of DLL3. immunotoxins had high expression and after purification under denaturing condition by Ni-NTA column, the immunotoxins were dialyzed against PBS buffer.Conclusion and implications:The immunotoxins had the right structure and can be produced in a prokaryotic host. The recombinant immunotoxins against DLL3 can be promising therapeutic agents for SCLC cancer.

01 Feb 2020·EBioMedicineQ1 · MEDICINE

Near infrared photoimmunotherapy targeting DLL3 for small cell lung cancer

Q1 · MEDICINE

ArticleOA

Author: Shimizu, Misae ; Baba, Yoshinobu ; Nakamura, Shota ; Isobe, Yoshitaka ; Taki, Shunichi ; Fukui, Takayuki ; Chen-Yoshikawa, Toyofumi F ; Takahashi, Kazuomi ; Yasui, Hirotoshi ; Hasegawa, Yoshinori ; Kuramoto, Noriko ; Kawaguchi, Koji ; Yukawa, Hiroshi ; Nishinaga, Yuko ; Sato, Kazuhide ; Endo, Rena ; Koike, Chiaki

BACKGROUNDSmall cell lung cancer (SCLC) has a poor prognosis, and its treatment options are limited. Delta-like protein 3 (DLL3) is expressed specifically in SCLC and is considered a promising therapeutic target for patients with this disease. Rovalpituzumab tesirine (Rova-T) was the first antibody-drug conjugate targeting DLL3. Although Rova-T development was unfortunately terminated, DLL3 remains an ideal target for SCLC. Near infrared photoimmunotherapy (NIR-PIT) is a new form of cancer treatment that employs an antibody-photosensitiser conjugate followed by NIR light exposure and damage target cells specifically. In this study, we demonstrate DLL3-targeted NIR-PIT to develop a novel molecularly targeted treatment for SCLC.METHODSThe anti-DLL3 monoclonal antibody rovalpituzumab was conjugated to an IR700 photosensitiser (termed 'rova-IR700'). SCLC cells overexpressing DLL3 as well as non-DLL3-expressing controls were incubated with rova-IR700 and then exposed to NIR-light. Next, mice with SCLC xenografts were injected with rova-IR700 and irradiated with NIR-light.FINDINGSDLL3-overexpressing cells underwent immediate destruction upon NIR-light exposure, whereas the control cells remained intact. The xenograft in mice treated with rova-IR700 and NIR-light shrank markedly, whereas neither rova-IR700 injection nor NIR-light irradiation alone affected tumour size.INTERPRETATIONOur data suggest that targeting of DLL3 using NIR-PIT could be a novel and promising treatment for SCLC.FUNDINGResearch supported by grants from the Program for Developing Next-generation Researchers (Japan Science and Technology Agency), KAKEN (18K15923, JSPS), Medical Research Encouragement Prize of The Japan Medical Association, The Nitto Foundation, Kanae Foundation for the Promotion of Medical Science.

10 Nov 2016·ACS Medicinal Chemistry LettersQ3 · MEDICINE

Design and Synthesis of Tesirine, a Clinical Antibody–Drug Conjugate Pyrrolobenzodiazepine Dimer Payload

Q3 · MEDICINE

Article

Author: Tiberghien, Arnaud C. ; Adams, Lauren R. ; Howard, Philip W. ; Williams, David G. ; Levy, Jean-Noel ; Corbett, Simon ; Hartley, John A. ; Masterson, Luke A. ; Patel, Neki V.

Pyrrolobenzodiazepine dimers are an emerging class of warhead in the field of antibody-drug conjugates (ADCs). Tesirine (SG3249) was designed to combine potent antitumor activity with desirable physicochemical properties such as favorable hydrophobicity and improved conjugation characteristics. One of the reactive imines was capped with a cathepsin B-cleavable valine-alanine linker. A robust synthetic route was developed to allow the production of tesirine on clinical scale, employing a flexible, convergent strategy. Tesirine was evaluated in vitro both in stochastic and engineered ADC constructs and was confirmed as a potent and versatile payload. The conjugation of tesirine to anti-DLL3 rovalpituzumab has resulted in rovalpituzumab-tesirine (Rova-T), currently under evaluation for the treatment of small cell lung cancer.

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