The present invention relates to a prodrug or a pharmaceutically acceptable salt thereof comprising a drug linker conjugate D-L, wherein -D is an amine containing biologically active moiety; and -L is a non-biologically active linker moiety -L.sup.1 represented by formula (I):

##STR00001##

wherein the dashed line indicates the attachment to the amine of the biologically active moiety and wherein R.sup.1, R.sup.1a, R.sup.2, R.sup.2a, R.sup.3, R.sup.3a, X, X.sup.1, X.sup.2, X.sup.3 have the meaning as indicated in the description and the claims and wherein L.sup.1 is substituted with one to four groups L.sup.2-Z and optionally further substituted, provided that the hydrogen marked with the asterisk in formula (I) is not replaced by a substituent; wherein L.sup.2 is a single chemical bond or a spacer; and Z is a carrier group. The invention also relates to A-L, wherein A is a leaving group, pharmaceutical composition comprising said prodrugs and their use as medicaments.

The present invention relates to a prodrug or a pharmaceutically acceptable salt thereof comprising a drug linker conjugate D-L, wherein -D is an amine containing biologically active moiety; and -L is a non-biologically active linker moiety -L.sup.1 represented by formula (I):

##STR00001##

wherein the dashed line indicates the attachment to the amine of the biologically active moiety and wherein R.sup.1, R.sup.1a, R.sup.2, R.sup.2a, R.sup.3, R.sup.3a, X, X.sup.1, X.sup.2, X.sup.3 have the meaning as indicated in the description and the claims and wherein L.sup.1 is substituted with one to four groups L.sup.2-Z and optionally further substituted, provided that the hydrogen marked with the asterisk in formula (I) is not replaced by a substituent; wherein L.sup.2 is a single chemical bond or a spacer; and Z is a carrier group. The invention also relates to A-L, wherein A is a leaving group, pharmaceutical composition comprising said prodrugs and their use as medicaments.

The present invention concerns novel and improved antibody-conjugates for targeting HER2. The inventors found that when antibody-conjugates were prepared using a specific mode of conjugation, they exhibit an improved therapeutic index. The mode of conjugation comprises a first step (i) of contacting a glycoprotein comprising 1-4 core N-acetylglucosamine moieties with a compound of the formula S(F.sup.1).sub.x—P in the presence of a catalyst, wherein S(F.sup.1).sub.x is a sugar derivative comprising x functional groups F1 capable of reacting with a functional group Q.sup.1, x is 1 or 2 and P is a nucleoside mono- or diphosphate, and wherein the catalyst is capable of transferring the S(F.sup.1).sub.x moiety to the core-GlcNAc moiety, to obtain a modified antibody; and a second step (ii) of reacting the modified antibody with a linker-conjugate comprising a functional group Q.sup.1 capable of reacting with functional group F.sup.1 and a target molecule D connected to Q.sup.1 via a linker L.sup.2 to obtain the antibody-conjugate wherein linker L comprises S—Z.sup.3-L.sup.2 and wherein Z.sup.3 is a connecting group resulting from the reaction between Q.sup.1 and F.sup.1. The invention also relates to a use for improving the therapeutic index of an antibody-conjugate and to a method for targeting HER2-expressing cells.

The present invention concerns novel and improved antibody-conjugates for targeting HER2. The inventors found that when antibody-conjugates were prepared using a specific mode of conjugation, they exhibit an improved therapeutic index. The mode of conjugation comprises a first step (i) of contacting a glycoprotein comprising 1-4 core N-acetylglucosamine moieties with a compound of the formula S(F.sup.1).sub.x—P in the presence of a catalyst, wherein S(F.sup.1).sub.x is a sugar derivative comprising x functional groups F1 capable of reacting with a functional group Q.sup.1, x is 1 or 2 and P is a nucleoside mono- or diphosphate, and wherein the catalyst is capable of transferring the S(F.sup.1).sub.x moiety to the core-GlcNAc moiety, to obtain a modified antibody; and a second step (ii) of reacting the modified antibody with a linker-conjugate comprising a functional group Q.sup.1 capable of reacting with functional group F.sup.1 and a target molecule D connected to Q.sup.1 via a linker L.sup.2 to obtain the antibody-conjugate wherein linker L comprises S—Z.sup.3-L.sup.2 and wherein Z.sup.3 is a connecting group resulting from the reaction between Q.sup.1 and F.sup.1. The invention also relates to a use for improving the therapeutic index of an antibody-conjugate and to a method for targeting HER2-expressing cells.

Provided herein, in some aspects, are delivery vehicles comprising a glycosphingolipid and an agent to be delivered attached to the glycosphingolipid. In some embodiments, the glycosphingolipid comprises an oligosaccharide and a short chain (e.g., C0-C3) ceramide. In some embodiments, the agent to be delivered is a therapeutic agent. The glycosphingolipid is able to deliver the agent to a cell or to a cellular compartment, as well as across the musical barrier. In some embodiments, agents delivered using the glycosphingolipid described herein exhibit longer half-life, compared to agents delivered alone. Methods of delivering a therapeutic agent to a subject for treating a disease using the glycosphingolipid delivery vehicle are also provided.

The invention provides a new oligopeptide linker intermediate and a preparation method thereof. The preparation method of the oligopeptide intermediate is easily carried out under mild reaction conditions, and since almost no side reactions occur in the reaction, the method produces a high-purity product with fewer impurities and easy to be purified, achieving unexpected technical effects.

The invention provides a new oligopeptide linker intermediate and a preparation method thereof. The preparation method of the oligopeptide intermediate is easily carried out under mild reaction conditions, and since almost no side reactions occur in the reaction, the method produces a high-purity product with fewer impurities and easy to be purified, achieving unexpected technical effects.

The present invention provides supramolecular filament and/or sphere compositions and their use as inhalable drug carriers within aerosols. The invention provides insights into peptide designs and supramolecular stability and its crucial role in the interfacial stability and aerosolization properties of the supramolecular filament and/or sphere compositions. The compositions and their properties show that molecular enrichment at the air-liquid interface during nebulization is the primary factor to deplete the monomeric peptide amphiphiles in solution, accounting for the observed morphological disruption/transitions. Importantly, encapsulation of drugs and dyes within the inventive filament and/or sphere compositions notably stabilize their supramolecular structure during nebulization, and the loaded filaments exhibit a linear release profile from a nebulizer device. The compositions disclosed herein can be used as an effective platform for the inhalation-based treatment of many lung and sinusoidal diseases.

The present invention provides supramolecular filament and/or sphere compositions and their use as inhalable drug carriers within aerosols. The invention provides insights into peptide designs and supramolecular stability and its crucial role in the interfacial stability and aerosolization properties of the supramolecular filament and/or sphere compositions. The compositions and their properties show that molecular enrichment at the air-liquid interface during nebulization is the primary factor to deplete the monomeric peptide amphiphiles in solution, accounting for the observed morphological disruption/transitions. Importantly, encapsulation of drugs and dyes within the inventive filament and/or sphere compositions notably stabilize their supramolecular structure during nebulization, and the loaded filaments exhibit a linear release profile from a nebulizer device. The compositions disclosed herein can be used as an effective platform for the inhalation-based treatment of many lung and sinusoidal diseases.

Among other things, the present disclosure provides technologies for site-directed conjugation of various moieties of interest to target agents. In some embodiments, the present disclosure utilizes target binding moieties to provide high conjugation efficiency and selectivity. In some embodiments, provided technologies are useful for preparing antibody conjugates.