Variant CD3-binding domains and their use in combination therapies for the treatment of disease

Inventors

Bonvini, Ezio • Huang, Ling • Lam, Chia-Ying Kao • Chichili, Gurunadh Reddy • Alderson, Ralph Froman • Moore, Paul A. • Johnson, Leslie S.

Assignees

Macrogenics Inc

Abstract

The present invention is directed to DA×CD3 Binding Molecules comprising a vCD3-Binding Domain, which comprises a CDRHI Domain, a CDRH2 Domain, a CDRH3 Domain, a CDRL I Domain, a CDRL2 Domain, and a CDRL3 Domain, at least one of which differs in amino acid sequence from the amino acid sequence of the corresponding CDR of a rCD3-Binding Domain, wherein the DA×CD3 Binding Molecule comprising such vCD3-Binding Domain exhibits an altered affinity for CD3, relative to a DA×CD3 Binding Molecule comprising such rCD3-Binding Domain. The invention particularly concerns to such DA×CD3 Binding Molecules comprising a vCD3-Binding Domain which exhibit reduced affinity for CD3 and are capable of mediating redirected killing of target cells expressing a DA and exhibit lower levels of cytokine release relative to a DA×CD3 Binding Molecule comprising a rCD3-Binding Domain. The invention particularly concerns the use of DA×CD3 Binding Molecules comprising a vCD3-Binding Domain in the treatment of cancer and pathogen-associated diseases. The present invention is also directed to pharmaceutical compositions that comprise such molecule(s).

Core Innovation

The invention relates to a Disease Antigen×CD3 (DA×CD3) binding molecule comprising a CD3-Binding Domain capable of binding an epitope of CD3 and a Disease Antigen-Binding Domain capable of binding an epitope of CD123. The CD3-Binding Domain is defined by specified complementarity-determining regions including CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, each comprising amino acid sequences identified by SEQ ID NO values. The molecule is configured as a binding construct that links defined CD123 and CD3 binding capabilities in a single DA×CD3 binding molecule.

The document also describes specific multichain architectures and explicitly defined polypeptide chains for CD123×CD3 binding. In one example, a TRIVALENT-type molecule is described as T-CD123-M18, comprising a CD123 mAb 1 VH/VL, a CD3 mAb 1 M18 VH/VL vCD3-binding domain, and TRX2 VH/VL, mapped to first, second, third, and fourth polypeptide chains using the recited SEQ ID NOs. This trivalent construct is presented within a broader context of building other trivalent redirected-killing molecules using alternative disease antigens and variant anti-CD3 domains.

The invention also concerns engineered IgG4 Fc CH2–CH3 amino acid variants that bias heterodimerization using knob-bearing versus hole-bearing mutations. The disclosure describes how heterodimerization is favored over homodimerization, and it includes Fc-containing molecules in multi-chain contexts together with trivalent binding molecules that include an Fc Domain and three epitope-binding sites.

Claims Coverage

The consolidated claim coverage identifies independent claim sets for a DA×CD3 binding molecule defined by specified CD3 CDR sequences and CD123-binding capability, a CD123×CD3 binding molecule defined by three specific polypeptide chain sequences, and an Fc heterodimerization-bias variant defined by knob-bearing versus hole-bearing CH2–CH3 mutations. Across these independent claims, the inventive features center on specified CDR sequences, defined polypeptide chain sequences, and heterodimerization-biased Fc CH2–CH3 variants.

Overall, the claims define CD3- and CD123-binding DA×CD3 constructs via explicit CDR and chain-sequence specifications, and further define Fc CH2–CH3 variants that bias heterodimerization through knob-bearing and hole-bearing mutations.

Stated Advantages

Documented Applications