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Bispecific antigen binding molecules with trivalent binding to cd40

An antigen-binding molecule and bispecific technology, which is applied in the fields of antibody medical components, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, medical preparations containing active ingredients, etc., can solve the problem of insufficient pathway activation, Issues such as narrow therapeutic index

Pending Publication Date: 2021-04-13
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Known CD40 antibodies can only be administered at relatively low doses due to dose-limiting toxicities such as cytokine release syndrome and platelet / endothelial cell activation, resulting in insufficient pathway activation on target APCs and a narrow therapeutic index

Method used

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  • Bispecific antigen binding molecules with trivalent binding to cd40
  • Bispecific antigen binding molecules with trivalent binding to cd40
  • Bispecific antigen binding molecules with trivalent binding to cd40

Examples

Experimental program
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example

[0523] The following are examples of methods and compositions of the present invention. It should be understood that various other embodiments may be practiced given the general description provided above.

[0524] recombinant DNA technology

[0525]Standard methods were used to manipulate DNA, as described in Sambrook et al., Molecular cloning: A laboratorymanual; Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989. Molecular biology reagents were used according to the manufacturer's instructions. General information on the nucleotide sequences of human immunoglobulin light and heavy chains is given in the following reference: Kabat, E.A. et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication No 91- 3242.

[0526] DNA sequencing

[0527] DNA sequence was determined by double-stranded sequencing.

[0528] gene synthesis

[0529] The desired gene segments were generated by PCR using appropriate templates, or synt...

example 1

[0542] Generation of new antibodies against fibroblast activation protein (FAP)

[0543] 1.1 Immunization of mice

[0544] Balb / c and NMRI mice were used for immunization. Animals were housed in an AAALACi accredited animal facility in accordance with Appendix A "Guidelines for the Accommodation and Care of Animals". All animal immunization protocols and experiments were approved by the Government of Upper Bavaria (license number 55.2-1-54-2531-19-10) and were performed in accordance with German Animal Welfare Act and European Parliament and Council Directive 2010 / 63. 6-8 week old Balb / c and NMRI mice (n=5) received human fibroblast activation protein alpha (amino acids 27-759; accession number NP_004451) covalently linked to a His-tag (SEQ ID NO:93) Four rounds of immunizations with the extracellular domain. Mice were anesthetized with a mixture of oxygen and isoflurane prior to each immunization. For the first immunization, 30 μg protein in PBS pH 7.4 was mixed with an e...

example 2

[0620] Generation and Production of Humanized Variants of Anti-CD40 Antibody S2C6

[0621] 2.1 Generation of humanized variants of anti-CD40 antibody S2C6

[0622] 2.2.1 Methods

[0623]During the humanization of the anti-CD40 binder S2C6 comprising the VH of SEQ ID NO:51 and the VL of SEQ ID NO:52, in order to identify a suitable human acceptor framework, a combination of two methods was used. On the one hand, classical approaches are employed by finding an acceptor framework with high sequence homology, grafting CDRs onto this framework, and assessing which backmutations can be envisaged. More specifically, the impact of each amino acid difference of the identified framework from the parent antibody is judged on the structural integrity of the binding agent and, where appropriate, backmutations towards the parent sequence are introduced. Structural assessments were based on Fv region homology models of the parental antibody and its humanized version, created with an in-hou...

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Abstract

The invention relates to novel bispecific antigen binding molecules with trivalent binding to CD40 and monovalent binding to a target cell antigen and to methods of producing these molecules and to methods of using the same.

Description

technical field [0001] The present invention relates to novel bispecific antigen binding molecules with trivalent binding to CD40 and monovalent binding to target cell antigens, in particular fibroblast activation protein (FAP). The present invention further relates to methods of producing these molecules and methods of using them. Background technique [0002] During the generation of an effective adaptive immune response, multiple molecular signals are required. Signal one involves the binding of T cell antigen receptors (TCRs) to cognate antigens present on the surface of antigen presenting cells (APCs). Signal two consists of the engagement of costimulatory receptors with their respective ligands between T cells and APCs. One of the best-studied and most important co-stimulatory effectors is the tumor necrosis factor receptor (TNFR) family member CD40 and its ligand CD40L (Elgueta R. et al., Immunol Rev. 2009;229(1):152-72 ). Following naive T cell activation, severa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C07K16/40C07K16/46
CPCC07K16/2878C07K16/40C07K16/468C07K2317/24C07K2317/31C07K2317/33C07K2317/35C07K2317/52C07K2317/524C07K2317/526C07K2317/55C07K2317/56C07K2317/64C07K2317/66C07K2317/71C07K2317/74C07K2317/75C07K2317/77C07K2317/92C07K2317/94C07K2319/00A61K39/3955A61K45/06C07K2317/522C07K2317/565C07K2317/567C07K2317/73
Inventor H·杜尔M·拉普C·特朗普费尔勒P·乌马纳
Owner F HOFFMANN LA ROCHE & CO AG
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