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Heterodimeric antibodies that bind cd3 and tumor antigens

A heterodimer and antibody technology, applied in the direction of antibodies, anti-tumor drugs, antibody medical components, etc., can solve the problems of limited biophysics and pharmacokinetics, toxic effects, non-specific activation of bispecific antibodies, etc.

Active Publication Date: 2018-05-11
XENCOR
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Thus, while bispecific antibodies generated from antibody fragments are limited by biophysical and pharmacokinetic barriers, construction with full-length antibody-like forms has the disadvantage that they are multivalent in the absence of the primary target antigen. Binds co-target antigens, leading to nonspecific activation and possible toxic effects

Method used

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  • Heterodimeric antibodies that bind cd3 and tumor antigens
  • Heterodimeric antibodies that bind cd3 and tumor antigens
  • Heterodimeric antibodies that bind cd3 and tumor antigens

Examples

Experimental program
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Effect test

Embodiment 1

[0454] Embodiment 1: Transformation form

[0455] Production of bispecific antibodies

[0456] The schematic diagram of anti-CD38×anti-CD3 bispecific antibody is shown in FIG. 1 . The amino acid sequences of various transformed anti-CD38×anti-CD3 bispecific antibodies are listed in Figure 39 to Figure 43 middle. DNA encoding the three chains required for bispecific antibody expression was generated by gene synthesis (Blue Heron Biotechnology, Bothell, WA) and subcloned into the expression vector pTT5 using standard molecular biology techniques. Substitutions were introduced using site-directed mutagenesis (QuikChange, Stratagene, Cedar Creek, TX) or other gene synthesis and subcloning. DNA was transfected into HEK293E cells for expression, and the resulting protein was purified from the supernatant using protein A affinity chromatography (GE Healthcare) and cation exchange chromatography. The yield of protein A affinity purification is as follows Figure 35 shown. Catio...

Embodiment 2

[0460] Redirected T cell cytotoxicity

[0461] In vitro identification of redirected T cell cytotoxicity (RTCC) of an anti-CD38×anti-CD3 Fab-scFv-Fc bispecific antibody against the CD38+RPMI8266 myeloma cell line. 40k RPMI8266 cells were incubated with 400k human PBMCs for 96 hours. Measurement of RTCC by flow cytometry, as Figure 44 shown. CD69, Ki-67 and PI-9 expression of CD4+ and CD8+ T cells were also identified by flow cytometry, as Figure 45 shown.

[0462] Mouse Model of Anti-Tumor Activity

[0463] On the -23rd day, five NODscidγ (NSG) mice in each group were injected into the tail vein of four groups with 5×10 6 RPMI8226TrS tumor cells (multiple myeloma, expressing luciferase). On day 0, mice were intraperitoneally implanted with 10 × 10 6 Individual PBMCs. After PBMC implantation on day 0, test articles were administered weekly (days 0, 7) by intraperitoneal injection at dose levels as Figure 4 shown. Figure 46 The experimental design is outlined. By ...

Embodiment 3

[0469] CDR development of CD123

[0470] The starting point for developing the CDRs of the humanized CD123 antibody Fab is the variable and light chain regions of the 7G3 murine antibody, called "7G3H0L0", from ATCC HB-12009. However, initial humanization (H1_L1, see Figure 136 for sequence) resulted in a severe reduction in affinity (5 to 10 fold affinity, see Figure 156B and C ). This decrease in affinity is mainly due to humanization of the heavy chain, see H1_L0 constructs (eg first humanized heavy chain with murine light chain), the H1_L1 construct shows a full 10-fold decrease. Consistent with this was a 10-fold reduction in RTCC (redirected T cell cytotoxicity) potency, see Figure 156D , the test is aimed at KG1a cells expressing CD123.

[0471] Thus, two rounds of affinity / stabilization optimization were performed. Round 1 ("Library 1" see Figure 157 ) generated 108 variants including LDA, targeting and back substitutions, these were then affinity screened o...

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Abstract

The present invention is directed to novel heterodimeric antibodies.

Description

[0001] Cross References to Related Applications [0002] This application is required under 35 U.S.C. §119(e) and §120 U.S. Provisional Patent Application No. 62 / 159,111 filed May 8, 2015, U.S. Provisional Patent Application No. 62 / 251,005 filed November 4, 2015, 2015 Priority to U.S. Provisional Patent Application Nos. 62 / 250,971, filed November 4, 2015, U.S.S.N. 14 / 952,714, filed November 11, 2015, and PCT / US2015 / 062772, filed November 25, 2015, the entire contents of which are adopted This document is incorporated by reference in its entirety, in particular the drawings, description and claims therein. Background of the invention [0003] Antibody-based therapies have been successfully used to treat a variety of diseases, including cancer and autoimmune / inflammatory disorders. However, there is still a need for improvements to this class of drugs, especially to enhance their clinical efficacy. One avenue being explored is the engineering of additional and neoantigen-bindi...

Claims

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Application Information

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IPC IPC(8): A61K39/00C07K16/28C07K16/30C07K16/46
CPCC07K16/2809C07K16/2866C07K16/2803C07K16/2887C07K2317/31C07K2317/622C07K2317/565C07K2317/522C07K16/2896C07K16/30C07K16/468A61K2039/505C07K2317/24C07K2317/35C07K2317/526C07K2317/528C07K2317/55C07K2317/60C07K2317/73C07K2317/92C07K2317/90C07K2317/94A61P35/02
Inventor G·摩尔J·德拉莱斯M·贝尔尼特S·楚R·拉什德U·穆赫哈S-H·李
Owner XENCOR
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