B7-H3 directed antibody drug conjugates

Inventors

Loo, Deryk T. • Huang, Ling • Johnson, Leslie S. • SON, Thomas • Scribner, Juniper A. • Bonvini, Ezio

Assignees

Macrogenics Inc

Abstract

The present invention is directed to novel B7-H3-binding molecules capable of binding to human and non-human B7-H3, and in particular to such molecules that are cross-reactive with B7-H3 of a non-human primate (e.g., a cynomolgus monkey). The invention additionally pertains to B7-H3-binding molecules that comprise Variable Light Chain and/or Variable Heavy Chain (VH) Domains that have been humanized and/or deimmunized so as to exhibit a reduced immunogenicity upon administration to recipient subjects. The invention particularly pertains to bispecific, trispecific or multispecific B7-H3-binding molecules, including bispecific diabodies, BiTEs, bispecific antibodies, trivalent binding molecules, etc. that comprise: (i) such B7-H3-binding Variable Domains and (ii) a domain capable of binding to an epitope of a molecule present on the surface of an effector cell. The invention is also directed to pharmaceutical compositions that contain any of such B7-H3-binding molecules, and to methods involving the use of any of such B7-H3-binding molecules in the treatment of cancer and other diseases and conditions. The invention also particularly pertains to a molecule that comprises the human B7-H3 binding domain of a humanized anti-human B7-H3 antibody conjugated to at least one drug moiety (a “B7-H3-ADC”). The invention is also directed to pharmaceutical compositions that contain such B7-H3-ADCs, and to methods involving the use of any of such B7-H3-ADCs in the treatment of cancer and other diseases and conditions.

Core Innovation

The invention relates to an anti B7-H3 antibody drug conjugate (B7-H3-ADC) having a defined construct formula Ab-(LM)m-(D)n. Ab is a B7-H3 antibody or a B7-H3 binding fragment that binds to B7-H3 and comprises a Variable Light Chain domain comprising the amino acid sequence of SEQ ID NO:20 and a Variable Heavy Chain domain comprising the amino acid sequence of SEQ ID NO:21. The cytotoxic drug moiety D is covalently linked to Ab through a linker molecule LM.

LM comprises at least one bond or a Linker Molecule that covalently links Ab and D, and m is an integer between 0 and n to denote the number of Linker Molecules of the B7-H3-ADC. The number of cytotoxic drug moieties covalently linked to the B7-H3-ADC molecule is defined as n, where n is an integer between 1 and 10. The disclosed construct therefore specifies both the covalent architecture joining the antibody to the cytotoxic payload and the payload stoichiometry range.

The described embodiments further define linker-spacer architectures, including cleavable or peptidic linkers and self-eliminating spacer systems, and may include a maleimide linker moiety positioned relative to the cleavable linker and Ab. The payload classes described include tubulysins, auristatins, maytansinoids, calicheamicins, pyrrolobenzodiazepines, duocarmycins, and alternative duocarmycin-related prodrugs such as CC-1065 and CCV-1065.

Claims Coverage

The independent claim coverage centers on one B7-H3-ADC construct defined by the Ab-(LM)m-(D)n formula, with the antibody component specified by VL and VH amino-acid sequences and the linker and payload stoichiometry constrained by integer ranges. Two principal inventive features are present: the specified B7-H3 antibody component and the constrained covalent conjugate structure.

The claim coverage is centered on a precisely defined B7-H3-ADC molecular formula where the antibody component is restricted to VL and VH sequences, the cytotoxic payload is covalently attached via a linker molecule, and the number of drug moieties is limited to n between 1 and 10 with linker counts m constrained between 0 and n.

Stated Advantages

Documented Applications