The present disclosure provides an antibody-drug conjugate loaded with binary toxins. By connecting MMAF with another drug unit in series at the cysteine binding site on the antibody, the two can exert a significant synergistic effect, thereby effectively improving the effect of killing tumor cells. This provides a new solution for the development of high-efficiency and low-toxic ADCs.

The present invention relates to a conjugate in which FL118 is linked to an acid-sensitive linker, and an immunoconjugate using the same.

The present invention is characterized in that at least one FL118 drug of Formula 1 is linked to an antibody or antigen-binding site-containing fragment thereof through an acid-sensitive linker; wherein after being targeted to cancer cells by an antigen-binding site that targets an antigen of cancer cells, the acid-sensitive linker is degraded in acidic atmosphere around cancer (pH≤7) to free at least a part of the FL118 drug of Formula 1 and the free FL118 drug of Formula 1 penetrates a cell membrane and moves into the cells; and wherein FL118 drug of Formula 1 inhibits the action an efflux pump to enrich the intracellular free FL118 drug of Formula 1.

The present disclosure relates to the biopharmaceutical field, in particular, Exatecan derivatives, linker-payloads, and conjugates and thereof antibody-drug conjugates, and the corresponding preparing process and use thereof.

The present description relates to a conjugated compound an antibody covalently linked to enhancer moiety composed by a nuclear localization sequence (NLS), covalently linked to a sterol variant, such as cholic acid (ChAc) or a variant thereof. The enhancer moiety as encompassed herein is able to induce endosome escape of the compound-conjugates by direct membrane destabilization or indirectly by ROS and ceramide production which destabilize endosome-lysosome membrane. The conjugated compound can further comprise payload.

The present invention concerns an antibody-drug conjugate, having structure (1)

##STR00001##

wherein AB is an antibody; L.sup.1 and L.sup.2 are linkers; w is 0 or 1; Z is a connecting group obtained by a metal-free click reaction or by thiol ligation; each R.sup.17 is individually an amino acid side chain; n is an integer in the range of 1-5; A is a 5- or 6-membered aromatic or heteroaromatic ring; x is an integer in the range of 1-8; R.sup.21 is selected from H, R.sup.22, C(O)OH and C(O)R.sup.22, wherein R.sup.22 is C.sub.1-C.sub.24 (hetero)alkyl groups, C.sub.3-C.sub.10 (hetero)cycloalkyl groups, C.sub.2-C.sub.10 (hetero)aryl groups, C.sub.3-C.sub.10 alkyl(hetero)aryl groups and C.sub.3-C.sub.10 (hetero)arylalkyl groups, which optionally substituted and optionally interrupted by one or more heteroatoms selected from O, S and NR.sup.23 wherein R.sup.23 is independently selected from the group consisting of hydrogen and C.sub.1-C.sub.4 alkyl groups.

Provided herein are immunoconjugates comprising an anti-ROR1 antibody or an antigen-binding fragment thereof and an exatecan moiety or an analog thereof. These immunoconjugates are useful for treating ROR1-expressing cancers.

A pharmaceutical composition, wherein an anti-HER2 antibody-drug conjugate in which a drug-linker represented by the following formula (wherein A represents a connecting position to an anti-HER2 antibody) is conjugated to the anti-HER2 antibody via a thioether bond, and a HER dimerization inhibitor are administered in combination, and/or a method of treatment, wherein the anti-HER2 antibody-drug conjugate and a HER dimerization inhibitor are administrated in combination to a subject.

A method for producing an antibody-drug conjugate composition, comprising: (i) a step of reacting an antibody with a reducing agent to obtain an antibody having thiol groups; then (ii) a step of reacting drug-linker intermediates with the antibody having thiol groups obtained in the step (i), wherein the step (i) is carried out until the composition ratio of the antibody having four heavy-light interchain thiols and the composition ratio of the antibody having four heavy-heavy interchain thiols reach a steady value.

The disclosure relates to a bioactive molecule conjugate, preparation methods and use thereof, particularly relates to a novel bioactive molecule conjugate obtained by improving coupling of the drug and the targeting moiety in an ADC or SMDC, as well as its preparation method and use in the manufacture of a medicament for the treatment of a disease associated with an abnormal cell activity.

The present invention provides antibody-conjugates which are conjugated via the glycan and still bind to a cell comprising an Fc-gamma receptor. The antibody conjugates according to the invention have structure (1):

Ab-[(GlcNAc(Fuc).sub.b-(G).sub.e-(Su-(Z-L-(D).sub.r).sub.x).sub.s].sub.y   (1)

Herein, Ab is an antibody; GlcNAc is an N-acetylglucosamine moiety; Fuc is a fucose moiety; b is 0 or 1; G is a monosaccharide; e is an integer in the range of 4-10; Su is a monosaccharide; Z is a connecting group obtained by a cycloaddition or a nucleophilic reaction; L is a linker; D is a payload; s is 1 or 2; r is an integer in the range of 1-4; x is 1 or 2; y is 2 or 4.