Disclosed herein are immunoconjugates comprising a CD46 binding domain and effector agent. Further provided herein are methods of treating cancer comprising administering to a subject having cancer a pharmaceutical composition comprising immunoconjugates comprising a CD46 binding domain and effector agent.

A conjugate of formula (I): Ab-(DL).sub.p wherein: Ab is an antibody, or an active fragment of an antibody; DL is (II). ##STR00001##

This disclosure generally relates to novel processes for the preparation of drug linker compounds and compositions comprising such drug linker compounds. The presently disclosed methods for synthesizing Fmoc-Val-Cit-PABOH and related compounds have also been found to minimize formation of diastereomeric impurities.

Aspects of the disclosure relate to antibodies that bind to transferrin receptor (e.g., transferrin receptor 1) and complexes comprising the antibody covalently linked to a molecular payload. Methods of using the antibodies are also provided.

An antibody or antigen-binding portion thereof which binds to PSMA and comprises a heavy chain variable domain comprising the sequence given in SEQ ID NO:33, wherein SEQ ID NO:33 is: EVQLVQSGX.sup.9E X.sup.11KKPGASVKV SCKX.sup.24SGYTFT EYTIHWVX.sup.38QA X.sup.41 GKGLEWIGN INPNX.sup.55GGTTY NOKFEDRX.sup.68TX.sup.70 TVDKSTSTAY MELSSLRSED TAVYYCAAGW NFDYWGOGTT VTVSS wherein: X.sup.9 is A or P X.sup.11 is V or L X.sup.24 is A or T X.sup.38 is R or K X.sup.41 is P or H X.sup.55 is N or Q X.sup.68 is V or A; and X.sup.70 is I or L whereby the heavy chain variable domain comprises up to 3 amino acid sequence modification(s) between positions 1-30, 36-49, 67-98 and 105-115 of SEQ ID NO: 33. The invention also provides compounds that include the antibody or antigen-binding portion thereof, such as conjugates, and their use in the treatment or diagnosis of diseases, in particular cancers, particularly prostate cancer.

The invention provides a method for producing an immunoconjugate, the method comprising combining one or more compounds of Formula I and an antibody construct of Formula II to provide the immunoconjugate of Formula III, wherein TA is a therapeutic agent, L is a linker, r is an integer from 1 to 50, Ar is an aromatic moiety comprising a substituent selected from PEG, —SO.sub.2CX.sub.3, —NR.sub.3.sup.+, —NO.sub.2, —SO.sub.3R, —SO.sub.2R, —CN, —CX.sub.3, —PO.sub.3R.sub.2, —OPO.sub.3R.sub.2, and salts thereof, each R independently is H, CX.sub.3, or C.sub.1-C.sub.4 alkyl, each X independently is hydrogen or a halogen, Y is CH.sub.2, PEG, or a bond, n is an integer from 1 to 4, and PEG has the formula: —(CH.sub.2CH.sub.2O)m-(CH.sub.2).sub.p—, where p is an integer from 1 to 5 and m is an integer from 2 to 50. The invention also provides an immunoconjugate and a composition of immunoconjugates formed from said method.

##STR00001##

The invention provides immunoconjugates of Formula I comprising an antibody linked by conjugation to one or more 8-amido-2-aminobenzazepine derivatives. The invention also provides 8-amido-2-aminobenzazepine derivative intermediate compositions comprising a reactive functional group. Such intermediate compositions are suitable substrates for formation of the immunoconjugates through a linker or linking moiety. The invention further provides methods of treating cancer with the immunoconjugates.

The present invention relates to the combined use of a duocarmycin derivative-comprising antibody-drug conjugate and thiosulfate in the treatment of a tumor in a human, whereby the thiosulfate prevents or reduces unwanted non-target tissue toxicity of the antibody-drug conjugate.

Provided herein are linkers, linker-drug groups and anti-body-drug conjugates comprising hydrophilic groups.

The present disclosure relates to targeted drug conjugates comprising ALK5 inhibitors and targeting moieties that direct the ALK5 inhibitors to cells involved in fibrosis and cancer, for example myofibroblasts, activated fibroblasts and transitioning fibroblasts, and their uses, in particular wherein the ALK5 inhibitor is N-methyl-2-(4-(4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)phenoxy)ethan-1-amine.