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Engineered ph-dependent anti-CD3 antibodies and methods of production and use thereof

A technology of antibodies and antigens, applied in chemical instruments and methods, antibodies, anti-receptors/cell surface antigens/cell surface determinant immunoglobulins, etc.

Pending Publication Date: 2022-03-04
ADIMAB LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, many of these anti-CD3 antibodies have developability issues (such as those outlined above), and / or trigger cytokine production, often resulting in toxic cytokine release syndrome (CRS)

Method used

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  • Engineered ph-dependent anti-CD3 antibodies and methods of production and use thereof
  • Engineered ph-dependent anti-CD3 antibodies and methods of production and use thereof
  • Engineered ph-dependent anti-CD3 antibodies and methods of production and use thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0183] Example 1: Construction of an engineered pH-dependent CD3 library

[0184] The combinatorial histidine substitution library was derived from the parental anti-CD3 antibody clone ADI-26906 (antibody number 1 of Table 1). ADI-26906 was originally disclosed in PCT / US2018 / 031705, which is hereby incorporated herein by reference in its entirety (ADI-26906 is not pH engineered). Histidine incorporation was utilized using three library designs: 1) H3+L3 hopping double plus L1 single or double histidine (His) substitution (with and without NNK variegation adjacent to His), resulting in a theoretical diversity of 3.4x10 5 ;2) Premade H1 / H2 diversity library plus H3 skipping doublets, resulting in a theoretical diversity of 6.8x10 8 , and 3) H3+L3 NNK / His or His / NNK walking monomorphisms, resulting in a theoretical diversity of 1.2x10 5 . Libraries were generated and propagated as previously described (see eg, WO2009036379; WO2010105256; WO2012009568; Xu et al., Protein Eng Des...

Embodiment 2

[0193] Example 2: Determining the affinity of anti-CD3 antibodies to CD3

[0194] By measuring its kinetic constant (k a 、k d 、K D ) to determine the affinity of anti-CD3 antibodies for CD3 at pH 6.0 and 7.4. ForteBio affinity measurements were generally performed as previously described (Estep et al., MAbs. 2013 5(2):270-8). Briefly, ForteBio affinity measurements were performed by online loading of antibodies (IgG) onto AHC sensors. The sensor was equilibrated offline for 30 minutes in assay buffer and then monitored online for 60 seconds for baseline establishment. For affinity binding measurements, sensors with loaded IgG were exposed to 100 nM antigen (human or cynomolgus CD3) for 3 minutes, after which they were transferred to assay buffer for 3 minutes for off-speed measurements. Kinetic data were fitted using a 1:1 binding model in the data analysis software provided by ForteBio. Table 2 provides kinetic constants for selected clones. Table 3 provides the equili...

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Abstract

Provided are engineered pH-dependent anti-CD3 binding domains, and antibodies and / or antigen binding domains comprising the same, including multispecific antibodies, having, inter alia, desirable T cell activation and (re) guided target cell killing potency and developable profiles; as well as methods of their identification, isolation and production; and methods of making and using the same.

Description

[0001] related application [0002] This application claims priority to U.S. Provisional Application No. 62 / 858,968, filed June 7, 2019, the contents of which are incorporated by reference in their entirety. [0003] sequence listing [0004] This application contains a Sequence Listing, which has been filed electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on June 3, 2020, is named 1160430.002000.TXT and is 634,880 bytes in size. technical field [0005] In particular, the present invention relates to engineered pH-dependent anti-cluster of differentiation 3 (CD3) antibodies (including multispecific antibodies and functional fragments thereof), and methods and reagents for their identification, isolation, preparation and use. Background technique [0006] Cell proliferative disorders such as cancer are characterized by the uncontrolled growth of subpopulations of cells. They are the leading cause of death in ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/30C07K16/28C07K16/32
CPCC07K2317/92C07K2317/565C07K2317/14C07K16/2809C07K2317/55C07K2317/33C07K2317/24A61K2039/505
Inventor J·盖根B·普林茨R·佩哈尔
Owner ADIMAB LLC
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