title: An anti-CD3/anti-CLL-1 bispecific antibody for the treatment of acute myeloid leukemia.
abstract: Acute myeloid leukemia (AML) is a major unmet medical need. Most patients have poor long-term survival, and treatment has not significantly changed in 40 years. Recently, bispecific antibodies that redirect the cytotoxic activity of effector T cells by binding to CD3, the signaling component of the T-cell receptor, and a tumor target have shown clinical activity. Notably, blinatumomab is approved to treat relapsed/refractory acute lymphoid leukemia. Here we describe the design, discovery, pharmacologic activity, pharmacokinetics, and safety of a CD3 T cell-dependent bispecific (TDB) full-length human IgG1 therapeutic antibody targeting CLL-1 that could potentially be used in humans to treat AML. CLL-1 is prevalent in AML and, unlike other targets such as CD33 and CD123, is not expressed on hematopoietic stem cells providing potential hematopoietic recovery. We selected a high-affinity monkey cross-reactive anti-CLL-1 arm and tested several anti-CD3 arms that varied in affinity, and determined that the high-affinity CD3 arms were up to 100-fold more potent in vitro. However, in mouse models, the efficacy differences were less pronounced, probably because of prolonged exposure to TDB found with lower-affinity CD3 TDBs. In monkeys, assessment of safety and target cell depletion by the high- and low-affinity TDBs revealed that only the low-affinity CD3/CLL1 TDB was well tolerated and able to deplete target cells. Our data suggest that an appropriately engineered CLL-1 TDB could be effective in the treatment of AML.
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Leong
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Sukumaran
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA.
authors.forename: Maria
authors.initials: M
authors.lastname: Hristopoulos
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA.
authors.forename: Klara
authors.initials: K
authors.lastname: Totpal
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Stainton
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Lu
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA.
authors.forename: Alfred
authors.initials: A
authors.lastname: Wong
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA.
authors.forename: Lucinda
authors.initials: L
authors.lastname: Tam
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA.
authors.forename: Robert
authors.initials: R
authors.lastname: Newman
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Vuillemenot
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA.
authors.forename: Diego
authors.initials: D
authors.lastname: Ellerman
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA.
authors.forename: Chen
authors.initials: C
authors.lastname: Gu
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA.
authors.forename: Mary
authors.initials: M
authors.lastname: Mathieu
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Dennis
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA.
authors.forename: Allen
authors.initials: A
authors.lastname: Nguyen
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA.
authors.forename: Bing
authors.initials: B
authors.lastname: Zheng
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA.
authors.forename: Crystal
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA.
authors.forename: Genee
authors.initials: G
authors.lastname: Lee
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA.
authors.forename: Yu-Waye
authors.initials: YW
authors.lastname: Chu
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA.
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Prell
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA.
authors.forename: Kedan
authors.initials: K
authors.lastname: Lin
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Laing
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Polson
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D006801:Humans; D037181:Lectins, C-Type / Q000276:immunology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008252:Macaca fascicularis; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000276:immunology*
chemical_list: D018033:Antibodies, Bispecific; D000970:Antineoplastic Agents; C571163:CD33 protein, human; D037181:Lectins, C-Type; D063268:Sialic Acid Binding Ig-like Lectin 3