- A novel radioiodination reagent for protein radiopharmaceuticals with L- lysine as a plasma-stable metabolizable linkage to liberate m-iodohippuric acid after lysosomal proteolysis
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Radiochemical design of polypeptides using metabolizable linkages would be attractive to enhance target-selective localization of radioactivity for diagnostic and therapeutic nuclear medicine. However, while use of ester bonds as the linkage allows selective release of the designed radiometabolite from covalently conjugated polypeptide after lysosomal proteolysis in nontarget tissues, low plasma stability of ester bonds causes a decrease in radioactivity levels of the target. In pursuit of new metabolizable linkages that provide stable attachment of radiolabels with polypeptide in plasma while facilitating rapid and selective release of designed radiometabolites of rapid urinary excretion in lysosomes, a new radioiodination reagent with L-lysine as the metabolizable linkage to liberate m-iodohippuric acid (L- HML) was designed and synthesized. Stabilities of the metabolizable linkage in serum and cleavabilities of the linkage in lysosomal proteloysis in hepatic cells were investigated after conjugation of [131I]-L-HML iwht galactosyl-neoglycoalbumin (NGA). For comparison, a radioiodination reagent with an ester bond to release m-iodohippuric acid (MIH) was conjugated with NGA under similar conditions. When incubated in human serum, [131I-L-HML- NGA liberated less than 3% of the initial radioactivity after 24 h, whereas [125I]MIH-NGA released more than 60% of its radioactivity during the same interval. In biodistribution studies, [131I]-L-HML-NGA demonstrated radioactivity elimination from murien liver at a rate and excretion route similar to [125I]MIH-NGA. Analyses of murine urine after injection of [131I]-L-HML-NGA indicated a single radioactivity peak at fractions identical to those of m-iodohippuric acid. Biodistribution studies of radioiodinated NGAs with D-lysine or cadaverine as the linkages demonstrated a delayed elimination rate from murine liver with significantly higher radioactivity being excreted in the feces at 24 h postinjection. Thus, L-HML is the first reagent that allows stable attachment of radiolabel with polypeptide in serum while facilitating selective release of a radiometabolite with rapid urinary excretion from covalently conjugated polypeptides after lysosomal proteolysis at a rate similar to that of ester bonds. Thus, L-HML is potentially useful for the radioiodination of polypeptides for diagnostic and therapeutic purposes.
- Wakisaka, Kouji,Arano, Yasushi,Uezono, Takashi,Akizawa, Hiromichi,Ono, Masahiro,Kawai, Keiichi,Ohomomo, Yoshiro,Nakayama, Morio,Saji, Hideo
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- Design and synthesis of site directed maleimide bifunctional chelators for technetium and rhenium
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A new family of heterobifunctional linkers (L1-L9) containing a terminus consisting of a tridentate donor set for coordination of the {M(CO) 3}+ core (M = Tc, Re), and a thiol reactive maleimide group has been prepared conveniently and in high yield under Mitsunobu reaction conditions by the coupling of an appropriate alcohol derivative with maleimide. The rhenium complexes [Re(CO)3(Lx)]Br (x = 1-9) were prepared in good yields from the reactions of the ligands and (NEt4) 2[Re(CO)3Br3] in refluxing methanol. The ligands and their Re complexes were characterized by 1H and 13C NMR, IR, and ESI-MS. Ligand L4 and [Re(CO)3(L5)]Br have been structurally characterized by X-ray crystallography. Photoexcitation of solutions of the complexes [Re(CO)3(Lx)]Br (x = 4-6) gives rise to intense and prolonged luminescence at room temperature (fluorescence lifetimes of ca. 16 μs). The ligands and their Re complexes react smoothly at the maleimide linker with sulfhydryl groups of peptides and proteins at room temperature in phosphate-buffered saline (PBS, pH 7.4) to form stable thioether bioconjugates. The photoluminescence properties of the labeled conjugates are similar to those of the parent complexes, but with even longer lifetimes. The ligands can also be labeled at room temperature with 99mTc to give chemically robust complexes. The corresponding hydrazinonicotinamide derivative N-[5-(6′-hydrazinopyridine-3′-carbonyl)aminopentyl]-maleimide (L10) was also prepared. While coupling of L10 to cysteine ethylester and synthesis of the rhenium derivative [ReCl3(HYNIC-maleimide)2] were successfully accomplished, attempts to couple [ReCl3(HYNIC-maleimide) 2] to glutathione or BSA yielded intractable mixtures. The Royal Society of Chemistry 2005.
- Banerjee, Sangeeta Ray,Schaffer, Paul,Babich, John W.,Valliant, John F.,Zubieta, Jon
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- CONJUGATES
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The present invention provides a conjugate of formula (I) and itsuse in methods of treatment, and also methods for delivering an active agent into a cell. The methods may be used to deliver an active agent into a nematode, flatworm, parasite or bacterium. The conjugate of formula (I) is: (formula (I)), wherein -D- is C1-4 alkylene or C2-4 alkenylene, preferably C2-4 alkenylene, where the alkylene or alkenylene is optionally substituted with alkyl or halo; A- is an active agent for delivery; and -RA, -RB, -RT1, -RT2, -R1, -R2, -R3, -X- and -L- are as defined herein.
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- SILVESTROL ANTIBODY-DRUG CONJUGATES AND METHODS OF USE
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The invention relates generally to a silvestrol molecule activated with a leaving group. The invention further relates generally to an antibody-drug conjugate comprising an antibody conjugated by a linker to one or more silvestrol drug moieties and methods of treatment.
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Page/Page column 81
(2018/01/15)
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- CARBON MONOXIDE RELEASING NORBORNENONE COMPOUNDS
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The present invention provides organic compounds which are capable of releasing carbon monoxide under physiological conditions or pH trigger, and to the use of such compounds for conditioning a cell, tissue or organ, for example, to protect against ischaemic injury during a transplant event.
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Page/Page column 56; 118; 119
(2017/09/27)
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- QUATERNARY AMINE COMPOUNDS AND ANTIBODY-DRUG CONJUGATES THEREOF
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This invention relates to antibody-drug conjugates represented by Formula (I) Ab- (L-D)p, Ab is an antibody; p is 1-8; L-D is a chemical moiety represented by the following formula -Str-(Pep)-Sp-D; Str is a stretcher unit covalently attached to Ab; Pep is a linker; D is anti-tumor agent represented by the following formula wherein Rand Rare each independently Ct-C6alkyl, and Ris a non-hydrogen substituent; or Ris C1-C6alkyl, and Rand Rtogether with the N form a substituted C3-C7heterocycloalkyl ring; or R° is absent, and Rand Rtogether with the N form a substituted heteroaryl ring; Sp-D is a spacer moiety of fomula: This invention also relates to a method of treating cancer, use of antibody-drug conjugates of Formula (I) in therapy, and use of antibody-drug conjugates of Formula (I) in manufacturing a medicament for treating cancer. This invention also relates to method of preparing antibody-drug conjugates of Formula (I).
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(2016/06/28)
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- ANTI-STAPHYLOCOCCUS AUREUS ANTIBODY RIFAMYCIN CONJUGATES AND USES THEREOF
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The invention provides anti-Staphylococcus aureus antibody rifamycin antibiotic conjugates and methods of using same.
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(2016/06/28)
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- ANTIBODIES AND IMMUNOCONJUGATES
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The invention provides immunoconjugates and methods of using the same.
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Paragraph 00337; 00339
(2017/01/02)
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- ANTI-STAPHYLOCOCCUS AUREUS ANTIBODY RIFAMYCIN CONJUGATES AND USES THEREOF
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The invention provides rF1 antibody antibiotic conjugates and methods of using same.
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Page/Page column 89
(2016/06/28)
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- PEPTIDOMIMETIC COMPOUNDS AND ANTIBODY-DRUG CONJUGATES THEREOF
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This invention relates to peptidomimetic linkers and anti-body drug conjugates thereof, to pharmaceutical compositions containing them, and to their use in therapy for the prevention or treatment of cancer.
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Page/Page column 67; 68
(2015/07/07)
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- PEPTIDOMIMETIC COMPOUNDS AND ANTIBODY-DRUG CONJUGATES THEREOF
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This invention relates to peptidomimetic linkers and anti-body drug conjugates thereof, to pharmaceutical compositions containing them, and to their use in therapy for the prevention or treatment of cancer.
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Page/Page column 261; 262
(2015/07/07)
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- Preparation of asymmetric urea derivatives that target prostate-specific membrane antigen for SPECT imaging
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Prostate-specific membrane antigen (PSMA) has been identified as a diagnostic and therapeutic target for prostate cancer. (S)-2-[3-[(R)-1-Carboxy- 2-mercaptoethyl]ureido-pentanedioic acid (Cys-CO-Glu) were used to design novel PSMA targeting probes by nucleophilic conjugate addition between cysteine and maleimide based reagents. 3 ([123I]IGLCE) was synthesized by this strategy and showed high affinity for PSMA. Results of binding inhibition assays of these derivatives suggested the importance of an aromatic group and succinimide moiety for high affinity. [123I]3 was evaluated in vivo with PSMA positive LNCaP and PSMA negative PC-3 human prostate cancer xenograft bearing mice. [125I]3 accumulated in LNCaP tumors but not in PC-3 tumors, and the accumulation was inhibited by 2-(phosphonomethyl)pentanedioic acid (2-PMPA). Use of [123I]3 provided positive images of LNCaP tumors in single photon emission tomography scans. These results warrant further evaluation of [123I]3 and its derivatives as radiolabeled probes for the diagnosis of prostate cancer.
- Harada, Naoya,Kimura, Hiroyuki,Ono, Masahiro,Saji, Hideo
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p. 7890 - 7901
(2013/11/06)
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- Aminoalkylmaleimides and hapten and antigen derivatives derived therefrom as well as conjugates with peptides or proteins
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The invention concerns new aminoalkylmaleimides of the general formula I STR1 in which R1 and R2 are the same or different and represent hydrogen or a C1 -C4 alkyl group and A represents a straight-chain or branched, saturated or unsaturated alkylene group with 2 to 6 carbon atoms which is interrupted, if desired, by an oxygen or sulphur atom or a carbonyl group, as well as their corresponding acid addition salts. The present invention also concerns amidoalkylmaleimide derivatives formed from compounds of the general formula I and immunological binding partners. In addition, the invention concerns immunological conjugates which can be produced by reaction of the amidoalkylmaleimide derivatives with peptides or proteins. The subject matter of the present invention are also the corresponding processes of production of the compounds according to the present invention as well as the use of these conjugates in diagnostic methods of determination, in particular in immunoassays.
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