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Anti-CD38 human antibodies and uses thereof

a human antibody and anti-cd38 technology, applied in the field of anti-cd38 human antibodies, can solve the problems of inconvenient human administration, low affinity and efficacy of okt10, and achieve the effect of effectively mediating the killing of cd38-overexpressing cells

Active Publication Date: 2010-11-11
MORFOZIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011]It is an object of the invention to provide human and humanized antibodies that can effectively mediate the killing of CD38-overexpressing cells.

Problems solved by technology

However, we have found that OKT10, which has been in clinical testing, has a relatively low affinity and efficacy when analyzed as chimeric construct comprising a human Fc part.
Furthermore, OKT10 is a murine antibody rendering it unsuitable for human administration.

Method used

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  • Anti-CD38 human antibodies and uses thereof
  • Anti-CD38 human antibodies and uses thereof
  • Anti-CD38 human antibodies and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Antibody Generation from HuCAL Libraries

[0123]For the generation of therapeutic antibodies against CD38, selections with the MorphoSys HuCAL GOLD phage display library were carried out. HuCAL GOLD® is a Fab library based on the HuCAL® concept (Knappik et al., 2000; Krebs et al., 2001), in which all six CDRs are diversified, and which employs the CysDisplay™ technology for linking Fab fragments to the phage surface (Löbning, 2001).

A. Phagemid Rescue, Phage Amplification and Purification

[0124]HuCAL GOLD® phagemid library was amplified in 2×TY medium containing 34 μg / ml chloraunphenicol and 1% glucose (2×TY-CG). After helper phage infection (VCSM13) at an O600 of 0.5 (30 mint 37° C. without shaking; 30 min at 37° C. shaking at 250 rpm), cells were spun down (4120 g; 5 min; 4° C.), resuspended in 2×TY / 34 μg / ml chloramphenicol / 50 μg / ml kanamycin and grown overnight at 22° C. Phages were PEG-precipitated from the supernatant, resuspended in PBS / 20% glycerol and stored at −80° C. Phage amp...

example 2

Biological Assays

[0125]Antibody dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity was measured according to a published protocol based on flow-cytometry analysis (Naundorf et al., 2002) as follows:

ADCC:

[0126]For ADCC measurements, target cells (T) were adjusted to 2.0E+05 cells / ml and labeled with 100 ng / ml Calcein AM (Molecular Probes, C-3099) in RPMI164O medium (Pan biotech GmbH) for 2 minutes at room temperature. Residual calcein was removed by 3 washing steps in RPMI1640 medium. In parallel PBMC were prepared as source for (natural killer) effector cells (E), adjusted to 1.OE+07 and mixed with the labeled target cells to yield a final B:T-ratio of 50:1 or less, depending on the assay conditions. Cells were washed once and the cell-mix resuspended in 200 μl RPMI1640 medium containing the respective antibody at different dilutions. The plate was incubated for 4 hrs under standardized conditions at 37° C. and 5% CO2 in a humidified incubator. Prior to FAC...

example 3

Generation of Stable CD38-Transfectants and CD38 Fc-Fusion Proteins

[0130]In order to generate CD38 protein for panning and screening two different expression systems had to be established. The first strategy included the generation of CD38-Fc-fusion protein, which was purified from supernatants after transient transfection of HEK293 cells. The second strategy involved the generation of a stable CHO-K1-cell line for high CD38 surface expression to be used for selection of antibody-phages via whole cell panning.

As an initial step Jurkat cells (DSMZ ACC282) were used for the generation of cDNA (Invitrogen) followed by amplification of the entire CD38-coding sequence using primers complementary to the first 7 and the last 9 codons of CD38, respectively (primer MTE001 & MTE002rev; Table 4). Sequence analysis of the CD38-unsert confirmed the published amino acid sequence by Jackson et al. (1990) except for position 49 which revealed a glutamune instead of a tyrosine as described by Nata e...

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Abstract

The present invention provides recombinant antigen-binding regions and antibodies and functional fragments containing such antigen-binding regions that are specific for CD38, which plays an integral role in various disorders or conditions. These antibodies, accordingly, can be used to treat, for example, hematological malignancies such as multiple myeloma. Antibodies of the invention also can be used in the diagnostics field, as well as for investigating the role of CD38 in the progression of disorders associated with malignancies. The invention also provides nucleic acid sequences encoding the foregoing antibodies, vectors containing the same, pharmaceutical compositions and kits with instructions for use. The invention also provides isolated novel epitopes of CD38 and methods of use therefore

Description

[0001]This application claims priority to U.S. provisional application Nos. 60 / 541,911 filed Feb. 6, 2004, 60 / 547,584 filed Feb. 26, 2004, 60 / 553,948 filed Mar. 18, 2004, and 60 / 599,014 filed Aug. 6, 2004, the contents of which are incorporated herein in their entirety.BACKGROUND OF THE INVENTION[0002]CD38 is a type-II membrane glycoprotein and belongs to the family of ectoenzymes, due to its enzymatic activity as ADP ribosyl-cyclase and cADP—hydrolase. During ontogeny, CD38 appears on CD34+ committed stem cells and lineage-committed progenitors of lymphoid, erythroid and myeloid cells. It is understood that CD38 expression persists only in the lymphoid lineage, through the early stages of T- and B-cell development.[0003]The up-regulation of CD38 serves as a marker for lymphocyte activation—in particular B-cell differentiation along the plasmacytoid pathway. (Co-)receptor functions of CD38 leading to intracellular signaling or intercellular communication via its ligand, CD31, are po...

Claims

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Application Information

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IPC IPC(8): A61K39/395C07K16/46C07K16/18C07H21/04C07K14/705C07K7/08A61P35/04A61P29/00A61P7/00C12N15/63C12N1/21C12N5/10C40B20/00C07K16/00C07K16/28
CPCA61K2039/505C12N9/2497C07K16/2896C07K2316/95C07K2317/21C07K2317/24C07K2317/34C07K2317/55C07K2317/56C07K2317/565C07K2317/732C07K2317/74C07K2319/30C12Y302/02024C07K16/005A61P19/02A61P29/00A61P35/02A61P35/04A61P37/00A61P7/00C07K16/00C07K16/18C07K16/3061C07K16/40C07K2317/734C07K2317/92C07K2317/33C07K2317/52C07K2317/567
Inventor TESAR, MICHAELJAGER, UTE
Owner MORFOZIS AG
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