38923-08-9Relevant articles and documents
The chemistry of 5-oxodihydroisoxazoles VII1 conversion of heterocyclylisoxazol-5(2H)-ones to imidazoles by flash vacuum pyrolysis
Prager, Rolf H.,Singh, Yogendra
, p. 8147 - 8158 (1993)
A number of 5-oxo-2,5-dihydroisoxazoles, substituted with nitrogen heterocycles at N-2, have been subjected to flash vacuum pyrolysis. Annelated imidazoles are obtained in excellent yields, and are presumed to arise by intramolecular cyclisation of an imi
ANTIBODY-DRUG CONJUGATES COMPRISING ANTI-B7-H3 ANTIBODIES
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Page/Page column 149; 187, (2022/01/04)
The present disclosure relates to antibody-drug conjugates (ADCs) wherein one or more active agents are conjugated to an anti-B7-H3 antibody through a linker. The linker may comprise a unit that covalently links active agents to the antibody. The disclosure further relates to monoclonal antibodies and antigen binding fragments, variants, multimeric versions, or bispecifics thereof that specifically bind B7-H3, as well as methods of making and using these anti-B7-H3 antibodies and antigen-binding fragments thereof in a variety of therapeutic, diagnostic and prophylactic indications
Design, synthesis, and evaluation of linker-duocarmycin payloads: Toward selection of HER2-targeting antibody-drug conjugate SYD985
Elgersma, Ronald C.,Coumans, Ruud G. E.,Huijbregts, Tijl,Menge, Wiro M. P. B.,Joosten, John A. F.,Spijker, Henri J.,De Groot, Franciscus M. H.,Van Der Lee, Miranda M. C.,Ubink, Ruud,Van Den Dobbelsteen, Diels J.,Egging, David F.,Dokter, Wim H. A.,Verheijden, Gijs F. M.,Lemmens, Jacques M.,Timmers, C. Marco,Beusker, Patrick H.
, p. 1813 - 1835 (2015/06/16)
Antibody-drug conjugates (ADCs) that are currently on the market or in clinical trials are predominantly based on two drug classes: auristatins and maytansinoids. Both are tubulin binders and block the cell in its progression through mitosis. We set out to develop a new class of linker-drugs based on duocarmycins, potent DNA-alkylating agents that are composed of a DNA-alkylating and a DNA-binding moiety and that bind into the minor groove of DNA. Linker-drugs were evaluated as ADCs by conjugation to the anti-HER2 antibody trastuzumab via reduced interchain disulfides. Duocarmycin 3b, bearing an imidazo[1,2-a]pyridine-based DNA-binding unit, was selected as the drug moiety, notably because of its rapid degradation in plasma. The drug was incorporated into the linker-drugs in its inactive prodrug form, seco-duocarmycin 3a. Linker attachment to the hydroxyl group in the DNA-alkylating moiety was favored over linking to the DNA-binding moiety, as the first approach gave more consistent results for in vitro cytotoxicity and generated ADCs with excellent human plasma stability. Linker-drug 2 was eventually selected based on the properties of the corresponding trastuzumab conjugate, SYD983, which had an average drug-to-antibody ratio (DAR) of about 2. SYD983 showed subnanomolar potencies against multiple human cancer cell lines, was highly efficacious in a BT-474 xenograft model, and had a long half-life in cynomolgus monkeys, in line with high stability in monkey and human plasma. Studies comparing ADCs with a different average DAR showed that a higher average DAR leads to increased efficacy but also to somewhat less favorable physicochemical and toxicological properties. Fractionation of SYD983 with hydrophobic interaction chromatography resulted in SYD985, consisting of about 95% DAR2 and DAR4 species in an approximate 2:1 ratio and having an average DAR of about 2.8. SYD985 combines several favorable properties from the unfractionated ADCs with an improved homogeneity. It was selected for further development and recently entered clinical Phase I evaluation.