Novel anti-cancer agents, including, but not limited to, antibodies and immunoconjugates, that bind to human folate receptor 1 are provided. Methods of using the agents, antibodies, or immunoconjugates, such as methods of inhibiting tumor growth are further provided.

A tri-functional linker moiety: formula (I), where X and Y are linking chains, and its use for preparing dual-mechanistic drug conjugates, preferably in a site-specific manner.

##STR00001##

Provided herein are bispecific antigen-binding molecules that bind HER2 and methods of use thereof. The bispecific antigen-binding molecules comprise a first and a second antigen-binding domain, wherein the first and second antigen-binding domains bind to two different (preferably non-overlapping) epitopes of the extracellular domain of human HER2. The bispecific antigen-binding molecules cluster on the surface of HER2 IHC2+ and IHC3+ cells, and are internalized into the cellular lysosomes. Also included are antibody-drug conjugates (ADCs) comprising the antibodies or bispecific antigen-binding molecules provided herein linked to a cytotoxic agent, radionuclide, or other moiety, as well as methods of treating cancer in a subject by administering to the subject a bispecific antigen-binding molecule or an ADC thereof.

An antibody-drug conjugate (ADC) or a pharmaceutically acceptable salt thereof, is provided. The ADC includes a tetravalent monoclonal antibody conjugated to a cytotoxic drug by a chemical linker. The monoclonal antibody includes two long chains and four short chains. Each of the long chains includes a first segment and a second segment, the first segment located proximal to the N-terminus of the long chain, and the second segment located proximal to the C-terminus of the long chain. Each of the first segment and second segment pairs with one of the short chains to form an antigen-binding fragment domain, therefore forming four antigen-binding fragment domains having specificity toward the same antigen. Pharmaceutical composition including the ADC and methods of treating diseases using the compositions are also provided.

Provided herein are modified amino acids comprising a tetrazine groups according to Formula I: polypeptides, antibodies, payloads and conjugates comprising these modified amino acid residues derived from the modified amino acids, and methods of producing the polypeptides, antibodies, payloads and conjugates comprising the modified amino acid residues. The polypeptides, antibodies, payloads and conjugates are useful in methods of treatment and prevention, methods of detection and methods of diagnosis. ##STR00001##

Methods of producing, purifying, and formulating antibody drug conjugates (ADCs) are provided herein. The methods use continuous conjugation processes, single-pass tangential flow filtration, countercurrent diafiltration, and/or in-line process automation technologies. The methods decrease process times and costs and improve product consistency.

The present invention concerns novel and improved antibody-conjugates for targeting HER2. The inventors found N 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 SZ.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 CD30. 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 F.sup.1 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 SZ.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 CD30-expressing cells.

The present invention provides a conjugate and preparation method thereof, a pharmaceutical composition comprising the conjugate and use of the pharmaceutical composition in the manufacture of a medicament for the treatment or prevention of a disease.

This document provides methods and materials involved in binding a binder (e.g., an antibody, antigen binding fragment, antibody domain, CAR, cell engager, and/or ADC) to a CD66e polypeptide. For example, binders (e.g., antibodies, antigen binding fragments, antibody domains, CARs, cell engagers, and/or ADCs) that bind to a CD66e polypeptide and methods and materials for using one or more such binding molecules to treat a mammal (e.g., a human) having cancer are provided.