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Immunostimulatory multimer binding molecules

A technology combining molecules and polymers, applied in the field of p|, can solve problems such as toxicity limitations

Pending Publication Date: 2022-04-01
IGM BIOSCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Standalone immunotherapy using cytokines (e.g., IFN-α, IL-2, IL-12, IL-15, IL-21, or GM-CSF) has proven somewhat effective in treating cancer and infection, but Clinical outcome is often limited by toxicity associated with high plasma concentrations of off-target cytokines required for efficacy

Method used

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  • Immunostimulatory multimer binding molecules
  • Immunostimulatory multimer binding molecules
  • Immunostimulatory multimer binding molecules

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0216] Example 1: Constructs and Characterization of IgM-Based Immunomodulators (ISAs) with Modified J Chains Expressing IL-15 and IL-15Rα sushi Domains

[0217] For the production of IgM-based immunomodulators (ISAs), a gene expressing the sushi domain of mature human IL-15 (SEQ ID NO: 4) and human IL-15Rα (SEQ ID NO: 5) as a fusion protein was constructed and characterized as follows. Modified J chain. The starting point for the modified J chain is a variant of the mature human J chain comprising a Y to A amino acid substitution at position 102 ("Y102A" or "J*", the amino acid sequence of the variant is presented as SEQ ID NO :3), this substitution enhances the serum half-life of the IgM pentamer comprising the J chain variant. See PCT Publication No. WO 2019 / 169314A1. Initially, IgM antibodies comprising an antigen-binding domain that binds PD-L1 were combined with various fusion proteins comprising all three domains (J*, mature IL-15 (“I”), and IL-15Rα sushi domain) as ...

Embodiment 2

[0225] Example 2: Ki-67 In Vitro Potency Assay of IgM-Based ISA

[0226] The in vitro potency of the various IgM J*RI ISA constructs prepared in Example 1 was assessed in the Ki-67 proliferation assay as follows. This assay measures the proliferation of primary cells (huPBMC, human peripheral blood mononuclear cells) in response to IL-15. Binding of IL-15 to its receptor results in cell proliferation, which can be visualized by several techniques, one of which is the cell cycle-associated protein assay. The most commonly used cell cycle-related protein is Ki-67, which is only expressed in G1, S, G2 and M phases. Determination of Ki-67 protein levels in the nuclei of cytotoxic CD8 T cells and natural killer NK cells (cells physiologically expressing the β and γ subunits of the IL-15 receptor) by flow cytometry is used for actual cell proliferation Surrogate assay. figure 2 A schematic diagram of the assay is shown in .

[0227] Briefly, healthy donor PBMCs are incubated fo...

Embodiment 3

[0236] Example 3: Evaluation of ISAs comprising IL-15 variants with reduced receptor binding

[0237] In certain aspects, eg, to manage the potential toxicities of a therapeutic ISA, it may be desirable to modify the potency of the IL-15 ISA by reducing binding to the IL-15β / γ receptor. Nine residues in mature human IL-15 (SEQ ID NO: 4) were previously identified by others as having the ability to reduce receptor binding, see PCT Publication No. WO 2018 / 071918A1. These include IL-15N1D (SEQ ID NO: 57), N4D (SEQ ID NO: 58), D8N (SEQ ID NO: 59), D30N (SEQ ID NO: 60), D61N (SEQ ID NO: 61), E64Q (SEQ ID NO: 62), N65D (SEQ ID NO: 63), N72D (SEQ ID NO: 64) and Q108E (SEQ ID NO: 65). These mutated IL-15 sequences were incorporated with double mutations N4D / N65D (SEQ ID NO: 66) and N1D / N65D (SEQ ID NO: 67) and triple mutations D30N / E64Q / N65D (SEQ ID NO: 68) into the Modified J chain in J*RI configuration, resulting in a fusion protein having the sequence SEQ ID No: 7-18. A modified...

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PUM

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Abstract

The present disclosure provides multivalent binding molecules comprising a modified J chain comprising an immunostimulatory agent. Also provided are polynucleotides encoding the binding molecules or subunits thereof, as well as vectors and host cells comprising the polynucleotides. The present disclosure also provides methods for producing and / or using multivalent binding molecules comprising a modified J chain comprising an immunostimulatory agent.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Patent Application Serial No. 62 / 887,458, filed August 15, 2019, which is hereby incorporated by reference in its entirety. [0003] sequence listing [0004] This application contains a Sequence Listing that has been filed electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on August 13, 2020, is named 022WO1-Sequence-Listing and is 358,808 bytes in size. Background technique [0005] Multimerizable antibodies and antibody-like molecules (such as IgA and IgM antibodies) have emerged as promising drug candidates, for example, in the fields of immuno-oncology and infectious diseases, allowing improved specificity, improved avidity and binding of multiple binding target capabilities. See, eg, U.S. Patent Nos. 9,951,134 and 9,938,347, and PCT Publication Nos. WO 2016 / 141303, WO2016 / 154593, WO 2016 / 168758, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C07K16/46C12N15/13A61K39/00
CPCC07K16/2827C07K2317/52C07K2317/92C07K2319/00C07K14/7051C07K16/2878C07K16/2809C07K2317/622C07K2317/31A61K2039/505C07K14/5443C07K14/55C07K14/7155A61P35/00C07K2317/70C07K2317/94C07K16/2887C07K16/2875A61K38/00C07K2317/35C07K2317/53C07K2317/565C07K2317/74C07K2317/75C07K2317/76C07K2319/30C07K2319/33
Inventor R·巴利加T·吉封D·吴
Owner IGM BIOSCI INC
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