Seattle Genetics, Inc.

Seagen Inc.

Svetlana Doronina

Peter Senter

Brian E Toki

Toni Beth Kline

Paul Polakis

Mark X Sliwkowski

Allen J Ebens

Susan D Spencer

Robert Lyon

Timothy Bovee

Scott C Jeffrey

Damon L Meyer

Leonard G Presta

Alan F Wahl

Stephen C Alley

Charles G Cerveny

Peter D Senter

Philip Moquist

Lori Y O'Connell

Brian A Mendelsohn

Hydrophilic Linkers, Drug-Linker compounds, Drug-Ligand Conjugate compounds and Ligand-Linkers and methods of making and using the same are provided.

Hydrophilic antibody-drug conjugates

Ligand Drug Conjugates of hydrophobically-modified auristatin F compounds that exhibit cytotoxic activities towards targeted cells, including abnormal cells such as cancer cells, that are MDR+ while also exhibiting bystander activities towards nearby cells having lower expression of the moeity targeted by the Conjugate.

Hydrophobic Auristatin F compounds and conjugates thereof

Auristatin peptides, including MeVal-Val-Dil-Dap-Norephedrine (MMAE) and MeVal-Val-Dil-Dap-Phe (MMAF), were prepared and attached to Ligands through various linkers, including maleimidocaproyl-val-cit-PAB. The resulting ligand drug conjugates were active in vitro and in vivo.

Monomethylvaline compounds capable of conjugation to ligands

Auristatin peptide analogs of MeVal-Val-Dil-Dap-Phe (MMAF) are provided having C-terminal phenylalanine residue side chain replacements or modifications which are provided alone or attached to ligands through various linkers. The related conjugates can target specific cell types to provide therapeutic benefit.

Monomethylvaline compounds having phenylalanine side-chain modification at the C-terminus

Auristatin peptide analogs of MeVal-Val-Dil-Dap-Phe (MMAF) having a carboxylic acid equivalent at the C-terminal phenylalanine were prepared and attached to ligands through various linkers, including maleimidocaproyl-val-cit-PAB. The resulting ligand-drug conjugates were active in vitro and in vivo in inhibiting cell proliferation and are represented by the general structure ofL-[(LU)-(D)]wherein L- is Ligand unit; LU is a Linker unit (LU); v is 1; p is an number ranging from about 1 to about 20; and D is a drug moiety having the formula: wherein the moiety &#x2014;N(R)Zis a phenylalanine bioisostere, wherein Zis &#x2014;CH(R)Zso that the phenylalanine bioisostere has the structure of Formula A: and wherein the substituents R-R, Xand Zare as defined.

Methods of using monomethylvaline compositions having phenylalanine carboxy modifications at the C-terminus

The present invention provides Ligand-Drug Conjugates, Drug-Linkers, Linkers, and Ligand-Linker Conjugates comprising a self-stabilizing linker assembly component.

Self-stabilizing linker conjugates

Drug Linker compounds and Drug Linker Ligand conjugates are provided that have auristatins linked via the C-terminus. The conjugates show efficacy without the need for a self-immolative group to release the drug.

Auristatin drug linker conjugates

Drug-Linker-Ligand Conjugates are disclosed in which a Drug is linked to a Ligand via a peptide-based Linker unit. In one embodiment, the Ligand is an Antibody. Drug-Linker compounds and Drug compounds are also disclosed. Methods for treating cancer, an autoimmune disease or an infectious disease using the compounds and compositions of the invention are also disclosed.

Drug conjugates and their use for treating cancer, an autoimmune disease or an infectious disease

Auristatin peptide analogs of MeVal-Val-Dil-Dap-Phe (MMAF) having a carboxylic acid equivalent at the C-terminal phenylalanine were prepared and attached to ligands through various linkers, including maleimidocaproyl-val-cit-PAB. The resulting ligand drug conjugates were active in vitro and in vivo.

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Snohomish, WA, United States of America

Svetlana Doronina