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Anti-cd38 antibodies and fusions to attenuated interferon alpha-2b

A CD38-, antibody technology, applied in the direction of interferon, cytokines/lymphokines/interferons, antibodies, etc., can solve the problems of prolonging the half-life of IFN-α and not completely solving the problem of healthy cell activity

Active Publication Date: 2016-04-06
TEVA PHARMA AUSTRALIA PTY LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While this approach can lead to increased IFN activity against cancer cells, it does not fully address the unwanted activity of IFN on healthy cells
Fusion of IFN-α to the C-terminus of the heavy chain of IgG prolongs the half-life of IFN-α, leading to unwanted adverse events

Method used

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  • Anti-cd38 antibodies and fusions to attenuated interferon alpha-2b
  • Anti-cd38 antibodies and fusions to attenuated interferon alpha-2b
  • Anti-cd38 antibodies and fusions to attenuated interferon alpha-2b

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0153] Optimized X355 / 02-HC-L0-IFN-α(A145D) IgG4

[0154] Other anti-CD38-attenuated IFN fusion proteins are described in PCT Application No. PCT / AU2012 / 001323. These include the antibody construct designated X355 / 02-HC-L0-IFN-alpha (A145D) IgG4 in the PCT application. In this specification, X355 / 02-HC-L0-IFN-α(A145D) IgG4 has been renamed as A02.1. The heavy chain sequence of the antibody comprises the amino acid sequence of SEQ ID NO:11, and the light chain sequence comprises the amino acid sequence of SEQ ID NO:12. The variable light chain (SEQ ID NO: 14) of A02.1 was co-expressed with its variable heavy chain (SEQ ID NO: 13) of A02.1 which contained the substitution S228P (EU numbering) (SEQ ID NO: 3) was formatted on the human IgG4 constant region. This antibody is referred to herein as X02.1. A02.1 includes a fusion to IFN-α2b, while X02.1 does not, although both antibodies have identical heavy and light chain sequences.

[0155] A BLAST study against a database of ...

example 2

[0213]In silico immunogenicity analysis of the A02.1 light chain amino acid sequence

[0214] Putative immunogenic epitopes were identified in the light chain variable region amino acid sequence of A02.1 using Epibase analysis software (Lonza, UK). To remove putative immunogenic epitopes, substitutions were introduced into the A02.1 variable light chain (Figure 4). The light chain with lower predicted immunogenicity was co-expressed in HEK293E cells with the A02.12 heavy chain variable region (SEQ ID NO:34) fused to A145D - Attenuated IFN formatted on IgG4 constant region containing substitution S228P. The antibody variants produced are detailed in FIG. 10 .

[0215] Table 10

[0216]

[0217]

[0218]

[0219] The above antibodies were analyzed for protein expression, CD38 binding by SPR, and potency using cell culture supernatant screen, as described in Example 5. The results of these experiments are detailed in Table 11. These data indicate that some residue s...

Embodiment 3

[0225] Multiple amino acid substitutions resulted in optimized A02.1 variants

[0226] Highly Optimized Anti-CD38 Antibody and Anti-CD38 Attenuated IFN Fusion Protein by Combining Substitutions Improving Immunogenicity, Manufacturability or Potency of Anti-CD38 Antibodies As Described Above Into a Single Gene Structure given. Table 12 summarizes the substitutions of such combinations and details the heavy and light chain combinations that were co-expressed in HEK293E cells and subsequently tested.

[0227] Table 12

[0228]

[0229]

[0230]

[0231]

[0232] Each antibody described in Table 12 was analyzed for protein expression, CD38 binding by SPR and titers using cell culture supernatants. The generated data are provided in Table 13. These results demonstrate that in silico predicted beneficial combinatorial substitutions resulted in several anti-CD38 attenuated IFN fusion proteins expressed and functionally potent in annexin V, caspase and cell proliferatio...

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Abstract

Antibodies that specifically bind to CD38, as well as constructs comprising such antibodies fused to attenuated interferon alpha-2B proteins are provided. Anti-CD38-attenuated interferon alpha-2b fusion constructs may be used to inhibit proliferation in cancerous cells that express both CD38 and the receptor for IFN-alpha2b, as well as to induce apoptosis in such cells. Inhibition of proliferation and induction of apoptosis in cancerous cells may serve as the basis for the treatment of the underlying cancer.

Description

[0001] Sequence Listing Reference [0002] This application includes an electronically filed Sequence Listing as a text file entitled anti-CD38_antibody_ST25, created on April 29, 2013, and is 462,000 bytes in size. The Sequence Listing is incorporated herein by reference. technical field [0003] The present disclosure relates generally to the field of antibody engineering. More specifically, the invention relates to antibodies that specifically bind CD38, as well as structures comprising such antibodies and attenuated interferon-alpha ligands, and therapeutic methods using these structures. In these structures, the antibody directs the ligand to cells expressing CD38 and the ligand's receptor, and the attenuated interferon-alpha reduces interferon signaling in cells that do not express CD38. Background technique [0004] Throughout the specification, various publications are referenced, including patents, published applications, technical articles, scholarly articles, an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C07K14/00
CPCC07K16/2896C07K2317/21C07K2317/24C07K2317/41C07K2317/92C07K2319/00A61P35/00A61P35/02A61K38/00A61K38/212C07K14/56C07K2317/56C07K2319/74C07K14/00A61K39/39558A61K2039/505C07K2317/52
Inventor 亚当·克拉克马修·波拉德安东尼·杰拉德·道尔科莱特·贝伦斯津田·山岸小大卫·S·威尔逊莎拉·L·波格哲野·田浦
Owner TEVA PHARMA AUSTRALIA PTY LTD
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