Treatment of cancer using a cd33 chimeric antigen receptor

A technology of chimeric antigen receptors and binding domains, which can be used in the fields of antibody medical components, antibodies, gene therapy, etc., and can solve problems such as poor persistence and limitations

Active Publication Date: 2017-08-29
NOVARTIS AG +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Preclinical and clinical attempts to target at least 20 different surface molecules in a variety of malignancies have shown some activity, however these attempts are often limited by the poor persistence of infused CAR T cell products (Sadelain et al., 2009, Curr Opin Immunol 2009,21:215-23)

Method used

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  • Treatment of cancer using a cd33 chimeric antigen receptor
  • Treatment of cancer using a cd33 chimeric antigen receptor
  • Treatment of cancer using a cd33 chimeric antigen receptor

Examples

Experimental program
Comparison scheme
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Embodiment 3

[0520]Additional examples of CAR molecules or antibody fragments thereof are provided in Example 3. Murine and humanized forms of anti-CD33 antibody 2213 are disclosed. For example, Example 3 provides the following: 2213 nucleotide sequence of murine anti-CD33 IgG4 (SEQ ID NO: 138); 2213 CAR nucleotide sequence (SEQ ID NO: 139); 2213 CAR amino acid sequence (SEQ ID NO: 140) ; 2213 scFv nucleotide sequence (SEQ ID NO: 141); and 2213 scFv amino acid sequence (SEQ ID NO: 142); 2218 humanized anti-CD33 IgG4H nucleotide sequence (SEQ ID NO: 143).

[0521] Other embodiments disclosed in Example 3 include CAR molecules and anti-CD33 antibody fragments of Gemtuzumab ozogamicin previously marketed as Mylotarg (e.g., referred to herein as "human Humanized form as described in "My96"). The amino acid sequence of the anti-CD33 scFv of gemtuzumab ozogamicin (immunoconjugate targeting CD33) with 41BB and CD3ζ signaling domains is described in Example 3 and SEQ ID NO:145. The correspondin...

Embodiment 1

[1167] Example 1: Humanized CAR constructs

[1168] CD33 levels were measured by flow cytometry in primary proprietary samples from AML patients using commercially available antibodies (clone HIM3-4, eBioscience; or clone WM53, Biolegend). The results presented here demonstrate that CD33 is expressed in many primary AML patient samples (using standard side scatter 低 CD45 暗 Features (gated on AML blasts); n = 35-46 per group).

[1169] image 3 A schematic diagram of the CAR construct used in this example is shown in . All are second-generation CARs using 41BB and CD3ζ signaling. The scFv of CART33 was derived from clone MY9-6.

[1170] In vitro activity of CART33

[1171] The experiments described here measure CART33-mediated degranulation of T cells. CART33-transduced T cells and UTDT cells were incubated with the CD33+ cell line MOLM14 and the control ALL cell line NALM6 and CD107a degranulation was measured by flow cytometry. Expression of both the murine CART33 con...

Embodiment 2

[1197] Example 2: CAR Constructs

[1198] A fully human anti-CD33 single chain variable fragment (scFv) was generated and cloned into a lentiviral expression vector along with the intracellular CD3ζ chain and the intracellular co-stimulatory domain 4-1BB and given the names described in Table 1 (this is described in the Invention Details). shown in the description).

[1199] The order in which the VL domain and the VH domain appear in the scFv changes (i.e., VL-VH, or VH-VL orientation), and 3 or 4 copies of the "G4S" (SEQ ID NO: 25) subunit ( Wherein each subunit comprises the sequence GGGGS (SEQ ID NO:25) (for example, (G4S) 3 (SEQ ID NO:28) or (G4S) 4 (SEQ ID NO:27)) to link the variable domains to create the integrity of the scFv domains, as shown in Table 3.

[1200] The sequences of the human scFv fragments (SEQ ID NO: 39-83, including optional leader sequences) are provided in Table 2 herein (in the Detailed Description of the Invention). The sequences of the leader...

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Abstract

The disclosure provides compositions and methods for treating diseases associated with expression of CD33. The disclosure also relates to chimeric antigen receptor (CAR) specific to CD33, vectors encoding the same, and recombinant T cells comprising the CD33 CAR. The disclosure also includes methods of administering a genetically modified T cell expressing a CAR that comprises a CD33 binding domain.

Description

[0001] This application claims the priority of PCT Application No. PCT / CN2014 / 082589 dated July 21, 2014 and PCT Application No. PCT / CN2014 / 090504 dated November 6, 2014. The entire contents of these applications are incorporated herein by reference. [0002] sequence listing [0003] This application contains a Sequence Listing that has been filed electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on July 15, 2015, is named N2067-7047WO3_SL.txt and is 323,686 bits in size. technical field [0004] The present invention generally relates to the use of immune effector cells (e.g., T cells, NK cells) engineered to express chimeric antigen receptors (CARs) for the treatment of diseases associated with the expression of cluster of differentiation 33 protein (CD33) . Background of the invention [0005] Most acute myeloid leukemia (AML) patients are incurable with standard therapy (Mrozek et al., 2012, J Clin Oncol,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/62C07K14/705C07K14/715C07K14/725C07K16/28C07K16/30A61K35/28A61K39/395A61P35/00
CPCA61K35/28A61K39/39558C07K14/7051C07K14/70517C07K14/7056C07K14/70578C07K14/7151C07K16/2803C07K16/3061A61K38/00A61K2039/505A61K2039/5156C07K2317/33C07K2317/53C07K2317/21C07K2317/24C07K2319/70C07K2319/00C07K2319/03C07K2317/622C07K2317/73A61K2300/00A61K31/436A61K31/711A61K45/06A61P35/00A61P35/02A61P37/04A61P43/00A61P7/00A61K38/1774A61K38/1793A61K48/00C07K14/705C07K16/2851C07K16/30C07K2317/565C07K2319/33
Inventor J·布罗格顿H·艾伯斯巴赫S·吉尔D·格拉斯T·胡贝尔J·雅斯库S·肯德利安J·曼尼克M·C·米伦L·墨菲C·理查森R·辛格宋慧娟吴期隆张继全
Owner NOVARTIS AG
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