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Anti-Cll-1 antibodies and methods of use

A CLL-1 and antibody technology, applied in the field of anti-CLL-1 antibodies, can solve problems such as failure to improve patient outcomes

Active Publication Date: 2018-03-27
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the unconjugated anti-CD33 mAb lintuzumab responded with modest single-agent activity against AML and failed to improve patient outcomes when combined with conventional chemotherapy in two randomized trials

Method used

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  • Anti-Cll-1 antibodies and methods of use
  • Anti-Cll-1 antibodies and methods of use
  • Anti-Cll-1 antibodies and methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0394] Example 1: Anti-CLL-1 Antibodies

[0395] A. Monoclonal Antibody Generation

[0396] Monoclonal antibodies against human (hu) and cynomolgus (cyno) CLL-1 were generated using the following protocol by immunizing animals with N-terminal Flag expressed in a mammalian expression system (DYKDDDDK (SEQ ID NO: 108 )) of recombinant huCLL-1 and cynoCLL-1 ectodomain (ECD, amino acids 65-265 of huCLL-1 and amino acids 65-265 of cynoCLL-1). The huCLL1ECD protein (amino acids 65-265) contains one SNP, AAA (Lys, K) 244 -> CAA (GLN, Q), and has a minor allele frequency (MAF) of 29%.

[0397] Positive clones were expanded and rescreened for binding to huCLL-1 and cynoCLL-1 by ELISA and FACS. Five clones were identified: m3H10, m6E7, m20B1, m21C9, and m28H12, which were correlated with stable cell lines expressing recombinant human and cynomolgus CLL-1 (according to fluorescence-activated cell sorting (FACS)) and in acute myeloid leukemia tumors Tumor-derived CLL-1 expressed on cel...

Embodiment 2

[0438] Example 2: Efficacy of CLL1 T cell-dependent bispecific (TDB) antibodies

[0439] The following example shows that engineered T cell-dependent bispecific antibodies comprising binding determinants against human CLL-1 on one arm and anti-human CD3e on the other arm are potent immune modulatory molecules capable of redirecting The individual's immune system to kill acute myeloid leukemia tumor cells and normal CD14+ monocytes from a human donor. Killing or monitoring of AML tumor cell lines (EOL-1, HL-60, THP-1, U937, Nomo-1, PL-21, ML-2 and Molm-13) by monitoring untouched human CD8+ T cells TDB efficacy was demonstrated by autologous T cell killing of autologous CD14+ mononuclear cells in a human PBMC population.

[0440] The TDBs used in the examples below contain anti-CLL-1 mouse and humanized mAb clones from three different epitope bins: 1) 6E7 and / or 21C9, 2) 20B1, and 3) 28H12 ), and the high-affinity antibody 38E4v1 and the low-affinity antibody 40G5c (1.0 and 1...

Embodiment 3

[0475] Example 3: Toxicity, Toxicokinetics (TK), and PD Studies in Cynomolgus Monkeys

[0476] Anti-CLL-1 / CD3 TDB antibodies described above (h6E7A(6E7.L4H1eA54) x h40G5c (low affinity anti-human CD3ε arm) and h6E7A(6E7.L4H1eA54) x h38E4v1 (high affinity anti-human CD3ε arm)) to determine toxicity, toxicokinetics (TK), and pharmacodynamics (PD). The study was carried out using purpose-bred, naïve cynomolgus monkeys (Macaca fascicularis) of Mauritius origin. Animals selected for this study demonstrated expression of CLL-1 on circulating CD11b+ myeloid cells (granulocytes and monocytes) by flow cytometry. Four groups of male cynomolgus monkeys were administered vehicle or anti-CLL-1 / CD3 TDB antibody via a single intravenous infusion and studied for 8-29 days for target cell depletion and recovery, as summarized in Table 9.

[0477] Table 9: Study Design for Single-Dose Toxicity, TK, and PD Studies in Cynomolgus Monkeys

[0478]

[0479] Serum was collected at various time ...

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Abstract

The present invention relates to anti-CLL-1 antibodies including anti-CLL-1 antibodies comprising a CLL-1 binding domain and a CD3 binding domain (e.g., anti-CLL-1 / CD3 T cell dependent bispecific (TDB) antibody) and methods of using the same.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application No. 62 / 180,376, filed June 16, 2015, and US Provisional Application No. 62 / 307,003, filed March 11, 2016, which are hereby incorporated by reference in their entirety. [0003] sequence listing [0004] This application, containing a Sequence Listing, has been filed electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on June 7, 2016, is named P32920-WO_SL.txt and is 62,510 bytes in size. technical field [0005] The present invention relates to anti-CLL-1 antibodies, including anti-CLL-1 antibodies comprising a CLL-1 binding domain and a CD3 binding domain (eg, anti-CLL-1 / CD3 T cell-dependent bispecific (TDB) antibodies) and methods of use thereof. Background technique [0006] Cell proliferative disorders, such as cancer, are characterized by the uncontrolled growth of a subpopulation of cells....

Claims

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Application Information

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IPC IPC(8): A61K39/00A61P35/02C07K16/28C07K16/30
CPCC07K16/2809C07K16/2827C07K16/3061A61K2039/505A61K2039/507C07K2317/24C07K2317/31C07K2317/33C07K2317/34C07K2317/40C07K2317/526C07K2317/55C07K2317/73C07K2317/76C07K2317/77C07K2317/90C07K2317/92C07K2317/94C07K16/2851A61P35/00A61P35/02A61P37/02A61P37/04A61K39/3955A61K45/06A61K2039/57C07K16/2803C07K2317/14C07K2317/41C07K2317/52C07K2317/56
Inventor R·F·凯利S·R·梁W-C·梁M·马蒂厄A·G·波尔森Y·吴郑冰X·陈C·P·C·赵M·S·丹尼斯A·埃本
Owner F HOFFMANN LA ROCHE & CO AG
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