Antibody adjuvant conjugates

A technology of immunoconjugates and antibodies, applied in the field of immunoconjugates, can solve problems such as the inability of the immune system to recognize new antigens

Active Publication Date: 2019-06-04
THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Why and how the immune system fails to recognize neoantigens begins to be elucidated

Method used

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  • Antibody adjuvant conjugates
  • Antibody adjuvant conjugates
  • Antibody adjuvant conjugates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[1029]

[1030]

[1031] wherein X is halogen (eg, iodine, bromine, or chlorine); R' is H or sulfo; R" is optionally substituted aryl (eg, 3-carboxy-4-nitrophenyl) or optionally substituted Substituted heteroaryl (eg, pyridin-2-yl); R"' is optionally substituted alkyl (eg, methoxy); Z 1 ,Z 2 ,Z 3 and Z 4 as above; and the dotted line Indicates the point of attachment of the adjuvant moiety.

[1032] In some embodiments, the linker moiety-Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -for:

[1033]

[1034] where dotted line indicates the point of attachment of the adjuvant moiety, and the wavy line Indicates the point of attachment of the amino acid side chain in the antibody. In some such embodiments, the amino acid side chain is a cysteine ​​side chain or a modified lysine side chain containing a thiol group.

[1035] In some embodiments, the immunoconjugate has a structure according to Formula III:

[1036]

[1037] or a pharmaceutically acceptable salt thereof, wher...

Embodiment 1

[1489] Example 1: Imidazoquinolines for Antibody Conjugation

[1490] Synthesis of imidazoquinoline compounds with free amine groups (compound 1) or maleimide groups (compound 2) according to Scheme 1 allowed rapid assessment of linker technology and antibody-adjuvant immunoconjugate efficacy.

[1491] To determine whether adjuvant functionalization affects the ability of Compound 2 or Compound 1 to elicit immune activation prior to analysis via flow cytometry. Human antigen-presenting cells were stimulated with 10-fold serial dilutions of R848, compound 2, compound 1 or the control TLR agonist, CL307, for 18 hours. The data indicated that Compound 2 and Compound 1 performed similarly to R848 at each concentration measured ( Figure 4 ; compound 1 data not shown).

[1492] Afterwards, the ability of each functionalized TLR agonist to activate human TLR7 or TLR8 was directly assayed. HEK293 cells were co-transfected with human TLR7 or TLR8 or murine TLR7 and an inducible s...

Embodiment 2

[1495] Example 2: Preparation of antibody adjuvant conjugates

[1496] According to the general protocol outlined in Scheme 2A and Scheme 2B, compound 1 was modified with a non-cleavable crosslinker (SMCC, ThermoFisher Scientific) and a cleavable crosslinker (SPDP, ThermoFisher Scientific) in preparation for combination with rituximab conjugate.

[1497] Scenarios 2A and 2B

[1498]

[1499] Adjuvants with free amines (R848, compound 1, etc.) were linked to SMCC, SPDP, or other NHS-containing compounds by reacting the compounds at a 1:1 molar ratio in PBS, pH 7-7.5, or other suitable buffer Subconjugation. All reactions were protected from light and incubated at room temperature for 30 min. Where possible, adjuvant-crosslinker conjugates were purified via reverse phase high performance liquid chromatography (HPLC). Adjuvant-crosslinker conjugates were used immediately after conjugation as described below.

[1500] The adjuvant-linker composition was desalted with Z...

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Abstract

The invention provides an immunoconjugate comprising an antibody construct which includes an antigen binding domain and an Fc domain, an adjuvant moiety, and a linker, wherein each adjuvant moiety iscovalently bonded to the antibody via the linker. Methods for treating cancer with the immunoconjugates of the invention are also described.

Description

Background technique [0001] It is now well established that tumor growth requires the acquisition of mutations that promote immune escape. Even so, tumorigenesis leads to the accumulation of mutated or neoantigens that are readily recognized by the host immune system following ex vivo stimulation. Why and how the immune system fails to recognize neoantigens is beginning to be elucidated. Pioneering studies by Carmi et al. (Nature, Vol. 521: pp. 99-104, 2015) showed that delivery of neoantigens to activated dendritic cells via antibody-tumor immune complexes can overcome immune neglect. In these studies, simultaneous delivery of tumor-binding antibody and dendritic cell adjuvant via intratumoral injection achieved robust antitumor immunity. To reach inaccessible tumors and expand treatment options for cancer patients and other subjects, new compositions and methods for the delivery of antibodies and dendritic cell adjuvants are needed. Contents of the invention [0002] In...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00C07K16/30C07K16/28
CPCA61K39/44A61K39/39A61K39/3955A61K39/39558A61P35/00A61K2039/55511C07K16/30A61K47/6849A61K47/6851A61K47/6855A61K47/6801C07K2317/74C07K16/2887C07K16/3053C07K16/2818C07K16/2851C07K16/44C07K2317/52A61K2039/55561A61K2039/55572A61K2039/55516A61K2039/5555A61K47/55A61K47/6867C07K16/28
Inventor 迈克尔·纳撒尼尔·阿隆索埃德加·乔治·英格曼雪莱·艾琳·阿克曼贾斯丁·肯克尔亚瑟·李大卫·Y·杰克逊
Owner THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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