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Psma binding antibody and use thereof

A technology of antibody molecules and binding fragments, which can be applied to antibody medical components, anti-tumor drugs, drug combinations, etc., and can solve problems affecting in vivo efficiency and T cell exhaustion

Active Publication Date: 2018-10-23
DEUTES KREBSFORSCHUNGSZENT STIFTUNG DES OFFENTLICHEN RECHTS +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In addition to T cell activation induced by bona fide monomeric CD3 stimulation, a recent paper proposes another mechanism for off-target activation involving the targeting moiety of the bispecific antibody; if this moiety is induced by the bispecific Composed of single-chain fragments that aggregate on the surface of T-specific cells, the effector portion of the T-cell induces tonic signaling, leading to T-cell exhaustion (Long et al. Nat Med 2015; 6:581), which is achieved through traditional Barely detectable in short-term in vitro assays but severely impacts in vivo efficiency

Method used

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  • Psma binding antibody and use thereof
  • Psma binding antibody and use thereof
  • Psma binding antibody and use thereof

Examples

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Embodiment 1

[0214] Example 1: Generation, identification and production of 10B3 antibodies

[0215] Antibody 10B3 was produced after immunization of female BALB / c mice with irradiated PSMA-transfected Sp2 / 0 Ag14 cells (Sp2 / 0-Ag14 cells were obtained from ATCC, where they were obtained under the trade name CRL-1581 TM commercially available). Four days after the last immunization, splenocytes were fused with transfected Sp2 / 0 cells and cultured in HAT selection medium. Supernatants from growing hybridoma cells were screened for PSMA antibody production by flow cytometry using PSMA-transfected as well as non-transfected Sp2 / 0 cells. Stable monoclonal hybridoma cell lines were obtained after subcloning by limiting dilution. For antibody production, the hybridoma cells were adapted to advanced DMEM medium (Gibco, Thermo Scientific, Waltham, MA, USA02451) supplemented with 1% FCS (Biochrom GmbH, Berlin, Germany) to avoid contamination during purification. Bovine IgG contamination. Antibo...

Embodiment 2

[0216] Example 2: Generation of Humanized 10B3 Antibody

[0217] The 10B3 antibody was obtained by grafting the CDR region to the human variable kappa light chain IGKV3-20*02 (the sequence is deposited in the IMGT / LIGM database under the accession number L37729, see also Ichiyoshi Y., Zhou M., Casali P.A human anti-insulin IgG autoantibody apparently arises through clonal selection from aninsulin-specific 'germ-line' natural antibody template.Analysis by V genesegment reassortment and site-directed mutagenesis'J.Immunol.154(1):226-238(1995)) and variable Heavy chain sequence IGHV3-11*06 (this sequence is deposited in the IMGT / LIGM database under accession number AF064919, see also Watson C.T., et al. Complete haplotype sequence of the human immunoglobulin heavy-chain variable, diversity, and joining genes and characterization of allelic and copy-number variation.Am.J.Hum.Genet.92(4):530-546(2013)) and was humanized in the germline sequence. Note here that IMGT / LIGM-DB is an I...

Embodiment 3

[0219] Example 3: Generation of recombinant antibody molecules and off-target T cell activation by different PSMAxCD3 antibodies

[0220] For the construction of recombinant bispecific antibody molecules, the variable domains of PSMA antibodies J591 and 10B3 were fused with the human constant and variable regions of CD3 antibodies OKT3 or UCHT1 in the following order: VH-CH1-CH2mod-scFv(OKT3 / UCHT1 ) (for the Fabsc format), VH-CH1-CH2mod-CH3-scFv (OKT3 / UCHT1) (for the IgGsc format) (see also figure 1A and 1B). In these antibody molecules, the PMSA binding site exists as a Fab fragment, while the CD3 binding site exists as a scFv fragment (see again figure 1 A and 1B). To eliminate FcR binding, glycosylation sites and disulfide bond formation, the following modifications were introduced into the hinge region and CH2 domain of the Fabsc format (EU-index): C226S; C229S; E233P; L234V; L235A; ΔG236; D265G ; N297Q; A327Q; A330S (see also International Patent Application WO 2013 / 09...

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Abstract

The present invention provides a novel PSMA binding antibody termed 10B3 and pharmaceutical and diagnostic uses of the antibody 10B3. The PSMA antibody 10B3 does not cross-compete with the state of the art PMSA binding antibody J591 and has a reduced induction of antigen shift compared to J591 and a unique reactivity with squamous cell carcinoma (SCC) cells of different origin.

Description

technical field [0001] The present invention provides novel PSMA-binding antibodies. The PSMA antibody of the present invention does not cross-compete with the prior art PMSA-binding antibody J591 and has reduced induction of antigenic shift compared to J591 and has unique reactivity with squamous cell carcinoma (SCC) cells of different origin. Furthermore, the present invention relates to bispecific PSMAxCD3 antibody molecules. The invention also relates to methods for producing the antibody molecules of the invention as well as nucleic acids, vectors and host cells. The invention also relates to methods of treating or diagnosing diseases using the PMSA antibody molecules of the invention. Background technique [0002] Scientific work from the 1980s has established that bispecific antibodies against tumor-associated antigens (TAA) and T-cell receptor (TCR) / CD3-complexes are able to activate T cells, resulting in TAA-expressing tumor cells being activated T cells. Cell ly...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C07K16/30
CPCC07K16/2809C07K16/3069C07K16/3084C07K2317/24C07K2317/31C07K2317/55C07K2317/622C07K2317/73A61P35/00C07K16/28A61K39/001195A61K39/001194A61K2039/884A61K2039/572
Inventor 赫尔穆特·萨利赫法比安·沃格特古恩德拉姆·荣格拉提法·泽克里-梅雷夫
Owner DEUTES KREBSFORSCHUNGSZENT STIFTUNG DES OFFENTLICHEN RECHTS
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