The present invention relates to therapeutic ADCs comprising SN-38 attached to an anti-Trop-2 antibody or antigen-binding antibody fragment, more particularly sacituzumab govitecan. The ADC is administered to a subject with a Trop-2 positive cancer that is resistant to or relapsed from prior treatment with a checkpoint inhibitor. The therapy is effective to treat cancers that are resistant to checkpoint inhibitors.

The present invention discloses an antibody drug conjugate that targets MSLN. The present invention also disclosed a method of making the antibody drug conjugate (ADC). The present invention further discloses a novel MSLN antibody or a functional fragment thereof comprising engineered heavy and light chains.

Described herein is the use of rabbit hybridoma technology, along with a panel of truncated mesothelin domain fragments, to identify anti-mesothelin mAbs that bind specific regions of mesothelin. In one aspect of the present disclosure, the rabbit mAbs bind an epitope that is not part of Region I. In particular, the identified mAbs (YP187, YP223, YP218 and YP3) bind either Region II (391-486), Region III (487-581) or a native conformation of mesothelin with subnanomolar affinity. These antibodies do not compete for binding with the mesothelin-specific immunotoxin SS1P or mesothelin-specific antibody MORAb-009. In another aspect, disclosed is a high-affinity rabbit mAb that binds Region I of mesothelin (YP158). YP158 binds native mesothelin protein in cancer cells and tissues with high affinity and specificity.

The present disclosure relates to pyrrolobenzodiazepines (PBDs) having a labile C2 or N10 protecting group in the form of a linker to an antibody.

Cytotoxic conjugates comprising a cell binding agent and a cytotoxic agent, therapeutic compositions comprising the conjugate, methods for using the conjugates in the inhibition of cell growth and the treatment of disease, and a kit comprising the cytotoxic conjugate are disclosed are all embodiments of the invention. In particular, the cell binding agent is a monoclonal antibody, and epitope-binding fragments thereof, that recognizes and binds the CA6 glycotope. The present invention is also directed to humanized or resurfaced versions of DS6, an anti-CA6 murine monoclonal antibody, and epitope-binding fragments thereof.

This invention pertains to protein-drug conjugates that may be used in the treatment of cancers and to pharmaceutical compositions containing the same. The protein-drug conjugate has the following formula (I), wherein: L is a cysteine-containing protein residue linked through one or more of the cysteine groups of the protein, R.sub.1 is selected from the group consisting of arylene, arylene-heteroarylene, heteroarylene-arylene and heteroarylene, n is an integer from 0 to 5, p and q are independently 0 or 1, R.sub.2, R.sub.3 and Z are spacers, u is 0 or 1 and T is a cleavable unit sensitive to hydrolases, k is 1 or 2 and D is a cytotoxic drug residue selected from dolastatin residues, which may be identical to or different from each other when k is 2, m is the mean payload-to-protein ratio (PPR) of the conjugate, which ranges from 0.1 to 16. ##STR00001##

Conjugate compounds of formula (A): ##STR00001##
wherein: R.sup.2 is ##STR00002##  where R.sup.36a and R.sup.36b are independently selected from H, F, C.sub.1-4 saturated alkyl, C.sub.2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C.sub.1-4 alkyl amido and C.sub.1-4 alkyl ester or, when one of R.sup.36a and R.sup.36b is H, the other is selected from nitrile and a C.sub.1-4 alkyl ester; R.sup.6 and R.sup.9 are independently selected from H, R, OH, OR, SH, SR, NH.sub.2, NHR, NRR′, NO.sub.2, Me.sub.3Sn and halo; R.sup.7 is independently selected from H, R, OH, OR, SH, SR, NH.sub.2, NHR, NRR′, NO.sub.2, Me.sub.3Sn and halo; Y is selected from formulae A1, A2, A3, A4, A5 and A6: ##STR00003## ##STR00004## L is a linker connected to a cell binding agent; CBA is the cell binding agent; n is an integer selected in the range of 0 to 48; R.sup.A4 is a C.sub.1-6 alkylene group; either (a) R.sup.10 is H, and R.sup.11 is OH, OR.sup.A, where R.sup.A is C.sub.1-4 alkyl; or (b) R.sup.10 and R.sup.11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or (c) R.sup.10 is H and R.sup.11 is OSO.sub.zM, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation; R and R′ are each independently selected from optionally substituted C.sub.1-12 alkyl, C.sub.3-20 heterocyclyl and C.sub.5-20 aryl groups, and optionally in relation to the group NRR′, R and R′ together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered heterocyclic ring; wherein R.sup.16, R.sup.17, R.sup.19, R.sup.20, R.sup.21 and R.sup.22 are as defined for R.sup.6, R.sup.7, R.sup.9, R.sup.10, R.sup.11 and R.sup.2 respectively; wherein Z is CH or N; wherein T and T′ are independently selected from a single bond or a C.sub.1-9 alkylene, which chain may be interrupted by one or more heteroatoms e.g. O, S, N(H), NMe, provided that the number of atoms in the shortest chain of atoms between X and X′ is 3 to 12 atoms; and
X and X′ are independently selected from O, S and N(H).

The invention provides immunoconjugates comprising anti-HER2 antibodies and methods of using the same.

A therapeutic agent comprising a cell binding agent which binds the Receptor for Advanced Glycation End (RAGE) products linked to an anti-cancer drug, for use in the treatment of gynaecological cancer, endometriosis or polycystic ovary syndrome. Novel cell binding agents, pharmaceutical compositions and methods are also described and claimed.

Methods of administering immunoconjugates that bind to FOLR1 are provided. The methods comprise administering an anti-FOLR1 immunoconjugate to a person in need thereof, for example, a cancer patient, at a therapeutically effective dosing regimen that results in minimal adverse effects.