MacroGenics, Inc.
Variant CD3-Binding Domains and Their Use in Combination Therapies for the Treatment of Disease

Abstract:

The present invention is directed to DA.times.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.times.CD3 Binding Molecule comprising such vCD3-Binding Domain exhibits an altered affinity for CD3, relative to a DA.times.CD3 Binding Molecule comprising such rCD3-Binding Domain. The invention particularly concerns to such DA.times.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.times.CD3 Binding Molecule comprising a rCD3-Binding Domain. The invention particularly concerns the use of DA.times.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).