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US 2019/0336615 A1Published application
Tumor targeting conjugates and methods of use thereof
AssigneeSilverback Therapeutics, Inc.
InventorsPeter Armstrong Thompson, Philip Huat Seng Tan, Peter Robert Baum, Robert Finley Dubose, Craig Alan Coburn, Sean Wesley Smith
Life of this patent
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Abstract
Various compositions are disclosed. The compositions of conjugates comprising immune-stimulatory compounds are also provided. Additionally provided are the methods of preparation and use of the conjugates. This includes methods for treating disorders, such as cancer.
Claims130
A recombinant bispecific antibody, comprising:
- a) a target antigen binding domain, wherein the target antigen binding domain specifically binds to a tumor associated antigen;
- b) an effector antigen binding domain, wherein the effector antigen binding domain specifically binds to an antigen on an antigen presenting cell and wherein the antigen is a molecule on the antigen presenting cell;
- c) an Fc comprising domain;
- and
- d) an immune-stimulatory compound attached to the recombinant bispecific antibody by a linker;
- wherein the recombinant bispecific antibody induces greater immune cell activation when the recombinant bispecific antibody is bound to the tumor associated antigen and to the antigen on the antigen presenting cell as compared to when the recombinant bispecific antibody is bound to the antigen on the antigen presenting cell but not to the tumor associated antigen.
3 more elements
A recombinant bispecific antibody, comprising:
- a) a target antigen binding domain, wherein the target antigen binding domain specifically binds to a tumor associated antigen;
- b) an effector antigen binding domain, wherein the effector antigen binding domain specifically binds to an antigen on an antigen presenting cell and is an antibody antigen binding domain, wherein the antigen is a molecule on the antigen presenting cell;
- and
- c) a domain comprising an Fc region;
- wherein the recombinant bispecific antibody induces greater immune cell activation when the recombinant bispecific antibody is bound to the tumor associated antigen and to the antigen on the antigen presenting cell as compared to when the recombinant bispecific antibody is bound to the antigen on the antigen presenting cell but not to the tumor associated antigen.
2 more elements
A recombinant bispecific antibody, comprising:
- a) a target antigen binding domain, wherein the target antigen binding domain specifically binds to a tumor associated antigen;
- b) an effector antigen binding domain, wherein the effector antigen binding domain specifically binds to an antigen on an antigen presenting cell and is an antibody antigen binding domain, wherein the antigen is a molecule on the antigen presenting cell;
- and
- c) a domain comprising an Fc region;
- wherein the recombinant bispecific antibody induces greater immune cell activation in the presence of cells having cell surface tumor associated antigen and antigen presenting cells having cell surface antigen as compared to immune cell activation in the absence of cells having cell surface tumor associated antigen.
2 more elements
A recombinant bispecific antibody, comprising:
- a) a target antigen binding domain, wherein the target antigen binding domain specifically binds to a tumor associated antigen;
- b) an effector antigen binding domain, wherein the effector antigen binding domain specifically binds to an antigen on an antigen presenting cell and wherein the antigen is a molecule on the antigen presenting cell;
- and
- c) an Fc comprising domain;
- and
- d) an immune-stimulatory compound attached to the recombinant bispecific antibody by a linker;
- wherein the recombinant bispecific antibody induces greater immune cell activation in the presence of cells having cell surface tumor associated antigen and antigen presenting cells having cell surface antigen as compared to immune cell activation in the absence of cells having cell surface tumor associated antigen.
4 more elements
The recombinant bispecific antibody of claim 41, wherein the one or more amino acid substitutions comprise E233P, L234V, L235A, AG236, A327G, A330S, and P331S, according to the EU index of Kabat.
The recombinant bispecific antibody of any one of claims 1 and 4-52, wherein the immune-stimulatory compound is a damage-associated molecular pattern molecule or a pathogen-associated molecular pattern molecule.
The recombinant bispecific antibody of any one of claims 1 and 4-53, wherein the immune-stimulatory compound is a Toll-like receptor agonist, STING agonist, or RIG-I agonist.
The recombinant bispecific antibody of any one of claims 3-55, wherein the immune-stimulatory compound is a CpG oligonucleotide, Poly G10, Poly G3, Poly I:C, Lipopolysaccharide, zymosan, flagellin, Pam3CSK4, PamCysPamSK4, dsRNA, a diacylated lipopeptide, a triacylated lipoprotein, lipoteichoic acid, a peptidoglycan, a cyclic dinucleotide, a 5′ppp-dsRNA, S-27609, CL307, UC-IV150, imiquimod, gardiquimod, resiquimod, motolimod, VTS-1463GS-9620, GSK2245035, TMX-101, TMX-201, TMX-202, isatoribine, AZD8848, MEDI9197, 3M-051, 3M-852, 3M-052, 3M-854A, S-34240, KU34B, SB9200, SB11285, 8-substituted imidazo[1,5-a]pyridine, or CL663.
A method of making a recombinant bispecific antibody comprising:
- a) producing an antibody construct comprising:
- i) a target antigen binding domain, wherein the target antigen binding domain specifically binds to a tumor associated antigen;
- ii) an effector antigen binding domain, wherein the effector antigen binding domain specifically binds to an antigen on an antigen presenting cell and the antigen is a molecule on the antigen presenting cell, wherein the antigen is a molecule on the antigen presenting cell;
- iii) an Fc comprising domain;
- and
- b) linking an immune-stimulatory compound to the antibody construct, wherein the recombinant bispecific antibody induces greater immune cell activation when the recombinant bispecific antibody is bound to the tumor associated antigen and to the antigen on the antigen presenting cell as compared to when the recombinant bispecific antibody is bound to the antigen on the antigen presenting cell but not to the tumor associated antigen.
3 more elements
A conjugate comprising:
- a) an antibody construct comprising:
- i) first binding domain, wherein the first binding domain specifically binds to a tumor antigen;
- ii) a second binding domain, wherein the second binding domain specifically binds to an antigen on an antigen presenting cell, wherein the antigen is a molecule on the antigen presenting cell;
- and
- iii) an Fc domain;
- b) an immune-stimulatory compound;
- and
- c) a linker attaching the antibody construct to the immune-stimulatory compound, wherein the linker is covalently bound to the antibody construct and the linker is covalently bound to the immune-stimulatory compound, and wherein a molar ratio of immune-stimulatory compound to antibody construct is less than 8;
- wherein the first binding domain is attached to the Fc domain and the second binding domain is attached to the Fc domain or to a C-terminal end of a light chain of the first binding domain;
- wherein a Kd for binding of the Fc domain to an Fc receptor in a presence of the first binding domain and the second binding domain is no greater than about 100 times a Kd for binding of the Fc domain to the Fc receptor in an absence of the second binding domain;
- and
- wherein immune cell activation caused by the conjugate when bound to the tumor antigen as measured by a cytokine release assay is greater than immune cell activation in the absence of binding to the tumor antigen.
9 more elements
A conjugate comprising:
- a) an antibody construct comprising:
- i) first binding domain, wherein the first binding domain specifically binds to a tumor antigen;
- ii) a second binding domain, wherein the second binding domain specifically binds to an antigen on an antigen presenting cell, wherein the antigen is a molecule on the antigen presenting cell;
- and
- iii) an Fc domain;
- b) an immune-stimulatory compound;
- and
- c) a linker attaching the antibody construct to the immune-stimulatory compound, wherein the linker is covalently bound to the antibody construct and the linker is covalently bound to the immune-stimulatory compound, and wherein a molar ratio of immune-stimulatory compound to antibody construct is less than 8;
- wherein the first binding domain is attached to the Fc domain and the second binding domain is attached to the Fc domain or to a C-terminal end of a light chain of the first binding domain;
- wherein a Kd for binding of the Fc domain to an Fc receptor in a presence of the first binding domain and the second binding domain is no greater than about 100 times a Kd for binding of the Fc domain to the Fc receptor in an absence of the second binding domain;
- and
- wherein antigen presenting cells are conditionally activated when the conjugate is bound to the tumor antigen as measured by a cytokine release assay.
9 more elements
An antibody construct comprising:
- a) a first binding domain, wherein the first binding domain specifically binds to a tumor antigen;
- b) a second binding domain, wherein the second binding domain specifically binds to an antigen on an antigen presenting cell, wherein the antigen is a molecule on the antigen presenting cell;
- and
- c) an Fc domain;
- wherein the first binding domain is attached to the Fc domain and the second binding domain is attached to the Fc domain or to a C-terminal end of a light chain of the first binding domain, and wherein a Kd for binding of the Fc domain to an Fc receptor in a presence of the first binding domain and the second binding domain is no greater than about 100 times a Kd for binding of the Fc domain to the Fc receptor in an absence of the second binding domain.
2 more elements
An antibody construct for use in inducing immune cell activation comprising:
- a) a first binding domain, wherein the first binding domain specifically binds to a tumor antigen;
- b) a second binding domain, wherein the second binding domain specifically binds to an antigen on an antigen presenting cell, wherein the antigen is a molecule on the antigen presenting cell;
- and
- c) an Fc domain;
- wherein the first binding domain is attached to the Fc domain and the second binding domain is attached to the Fc domain or to a C-terminal end of a light chain of the first binding domain, and wherein a Kd for binding of the Fc domain to an Fc receptor in a presence of the first binding domain and the second binding domain is no greater than about 100 times a Kd for binding of the Fc domain to the Fc receptor in an absence of the second binding domain;
- and
- wherein immune cell activation caused by the antibody construct upon binding to tumor antigen as measured by a cytokine release assay is greater than immune cell activation caused by the antibody construct in the absence of binding to tumor antigen.
4 more elements
A conjugate for use in inducing immune cell activation comprising:
- a) an antibody construct comprising:
- i) first binding domain, wherein the first binding domain specifically binds to a tumor antigen;
- ii) a second binding domain, wherein the second binding domain specifically binds to an antigen on an antigen presenting cell, wherein the antigen is a molecule on the antigen presenting cell;
- and
- iii) an Fc domain;
- b) an immune-stimulatory compound;
- and
- c) a linker attaching the antibody construct to the immune-stimulatory compound, wherein the linker is covalently bound to the antibody construct and the linker is covalently bound to the immune-stimulatory compound, and wherein a molar ratio of immune-stimulatory compound to antibody construct is less than 8;
- wherein the first binding domain is attached to the Fc domain and the second binding domain is attached to the Fc domain or to a C-terminal end of a light chain of the first binding domain;
- wherein a Kd for binding of the Fc domain to an Fc receptor in a presence of the first binding domain and the second binding domain is no greater than about 100 times a Kd for binding of the Fc domain to the Fc receptor in an absence of the second binding domain;
- and
- wherein immune cell activation caused by the conjugate when bound to the tumor antigen as measured by a cytokine release assay is greater than immune cell activation in the absence of binding to the tumor antigen.
9 more elements
A conjugate for use in conditionally activating an antigen presenting cell comprising:
- a) an antibody construct comprising:
- i) first binding domain, wherein the first binding domain specifically binds to a tumor antigen;
- ii) a second binding domain, wherein the second binding domain specifically binds to an antigen on the antigen presenting cell, and
- iii) an Fc domain;
- b) an immune-stimulatory compound;
- and
- c) a linker attaching the antibody construct to the immune-stimulatory compound, wherein the linker is covalently bound to the antibody construct and the linker is covalently bound to the immune-stimulatory compound, and wherein a molar ratio of immune-stimulatory compound to antibody construct is less than 8;
- wherein the first binding domain is attached to the Fc domain and the second binding domain is attached to the Fc domain or to a C-terminal end of a light chain of the first binding domain;
- wherein a Kd for binding of the Fc domain to an Fc receptor in a presence of the first binding domain and the second binding domain is no greater than about 100 times a Kd for binding of the Fc domain to the Fc receptor in an absence of the second binding domain;
- and
- wherein antigen presenting cells are conditionally activated when the conjugate is bound to the tumor antigen as measured cytokine release assay.
8 more elements
The antibody construct or conjugate of any one of claims 68-79, wherein an amino acid sequence of the tumor antigen has at least 80% sequence identity with the amino acid sequence of a tumor antigen selected from TABLE 1.
The antibody construct or conjugate of any one of claims 68-81, wherein an amino acid sequence of the antigen on the antigen presenting cell has at least 80% sequence identity with the amino acid sequence of an antigen selected from the group consisting of CD40, DEC-205, CD36 mannose scavenger receptor 1, CLEC9A, DC-SIGN, CLEC12A, BDCA-2, OX40L, 41BBL, CD204, MARCO, CLEC5A, Dectin 1, Dectin 2, CLEC10A, CD206, CD64, CD32A, CD16A, HVEM, PD-L1, CD32B, and CD47, but not CD40 when the first binding domain specifically binds to HER2.
A conjugate comprising:
- a) an immune-stimulatory compound;
- b) an antibody construct comprising a first binding domain and an Fc domain, wherein the first binding domain specifically binds to an antigen expressed on a cell, wherein the amino acid sequence of the antigen has at least 80% homology to the amino acid sequence of an antigen selected from a group consisting of Endoglin, CD204, CD206, CD301, VTCN1, VISTA, GLP-3, CLDN6, CLDN16, UPK1B, STRA6, TMPRSS3, TMPRSS4, TMEM238, C1orf186, LRRC15, DEC-205, CD36 mannose scavenger receptor 1, CLEC9A, DC-SIGN, CLEC12A, BDCA-2, 41BBL, MARCO, CLEC5A, Dectin 1, Dectin 2, CD64, CD32A, CD16A, HVEM, and CD32B, and a fragment thereof;
- and
- c) a linker attaching the antibody construct to the immune-stimulatory compound, wherein the linker is covalently bound to the antibody construct and the linker is covalently bound to the immune-stimulatory compound, and wherein a molar ratio of immune-stimulatory compound to antibody construct is less than 8.
1 more element
A conjugate comprising:
- a) an immune-stimulatory compound;
- b) an antibody construct comprising a first binding domain and an Fc domain, wherein:
- i) the first binding domain specifically binds to an antigen, wherein the amino acid sequence of the antigen has at least 80% homology to the amino acid sequence of an antigen selected from a group consisting of endoglin, PD-L1, CD204, CD206, CD301, VTCN1, VISTA, GLP-3, CLDN6, CLDN16, UPK1B, STRA6, TMPRSS3, TMPRSS4, TMEM238, C1orf186, LRRC15, DEC-205, CD36 mannose scavenger receptor 1, CLEC9A, DC-SIGN, CLEC12A, BDCA-2, OX40L, 41BBL, MARCO, CLEC5A, Dectin 1, Dectin 2, CD64, CD32A, CD16A, HVEM, CD32B, and CD47, and a fragment thereof,
- ii) a Kd for binding of the first binding domain to the antigen in a presence of the immune-stimulatory compound is less than about 100 nM and no greater than about 100 times a Kd for binding of the first binding domain to the antigen in the absence of the immune-stimulatory compound, and
- iii) a Kd for binding of the Fc domain to an Fc receptor in the presence of the immune-stimulatory compound is no greater than about 100 times a Kd for binding of the Fc domain to the Fc receptor in the absence of the immune-stimulatory compound;
- and
- c) a linker attaching the antibody construct to the immune-stimulatory compound, wherein the linker is covalently bound to the antibody construct and the linker is covalently bound to the immune-stimulatory compound, and wherein a molar ratio of immune-stimulatory compound to antibody construct is less than 8.
4 more elements
A conjugate comprising:
- a) an immune-stimulatory compound;
- b) an antibody construct comprising a first binding domain and an Fc domain, wherein:
- i) the first binding domain comprises a variable region comprising a set of CDR sequences that comprises at least 80% sequence identity to a set of variable region CDR sequences set forth in TABLE 3 or TABLE 11;
- ii) a Kd for binding of the first binding domain to the antigen in a presence of the immune-stimulatory compound is less than about 100 nM and no greater than about 100 times a Kd for binding of the first binding domain to the antigen in the absence of the immune-stimulatory compound, and
- iii) a Kd for binding of the Fc domain to an Fc receptor in the presence of the immune-stimulatory compound is no greater than about 100 times a Kd for binding of the Fc domain to the Fc receptor in the absence of the immune stimulatory compound;
- and
- c) a linker attaching the antibody construct to the immune-stimulatory compound, wherein the linker is covalently bound to the antibody construct and the linker is covalently bound to the immune-stimulatory compound, and wherein a molar ratio of immune-stimulatory compound to antibody construct is less than 8.
4 more elements
A conjugate for use in activating an immune cell comprising:
- a) an immune-stimulatory compound;
- b) an antibody construct comprising a first binding domain and an Fc domain, wherein the first binding domain specifically binds to an antigen expressed on a cell, wherein the amino acid sequence of the antigen has at least 80% homology to the amino acid sequence of an antigen selected from a group consisting of Endoglin, CD204, CD206, CD301, VTCN1, VISTA, GLP-3, CLDN6, CLDN16, UPK1B, STRA6, TMPRSS3, TMPRSS4, TMEM238, C1orf186, LRRC15, DEC-205, CD36 mannose scavenger receptor 1, CLEC9A, DC-SIGN, CLEC12A, BDCA-2, 41BBL, MARCO, CLEC5A, Dectin 1, Dectin 2, CD64, CD32A, CD16A, HVEM, and CD32B, and a fragment thereof;
- and
- c) a linker attaching the antibody construct to the immune-stimulatory compound, wherein the linker is covalently bound to the antibody construct and the linker is covalently bound to the immune-stimulatory compound, and wherein a molar ratio of immune-stimulatory compound to antibody construct is less than 8;
- and
- wherein immune cell activation caused by the conjugate when bound to the tumor antigen as measured by a cytokine release assay is greater than immune cell activation is greater than immune cell activation in the absence of binding to the tumor antigen.
3 more elements
A conjugate for use in activating an immune cell comprising:
- a) an immune-stimulatory compound;
- b) an antibody construct comprising a first binding domain and an Fc domain, wherein:
- i) the first binding domain specifically binds to an antigen, wherein the amino acid sequence of the antigen has at least 80% homology to the amino acid sequence of an antigen selected from a group consisting of endoglin, PD-L1, CD204, CD206, CD301, VTCN1, VISTA, GLP-3, CLDN6, CLDN16, UPK1B, STRA6, TMPRSS3, TMPRSS4, TMEM238, C1orf186, LRRC15, DEC-205, CD36 mannose scavenger receptor 1, CLEC9A, DC-SIGN, CLEC12A, BDCA-2, OX40L, 41BBL, MARCO, CLEC5A, Dectin 1, Dectin 2, CD64, CD32A, CD16A, HVEM, CD32B, and CD47, and a fragment thereof,
- ii) a Kd for binding of the first binding domain to the antigen in a presence of the immune-stimulatory compound is less than about 100 nM and no greater than about 100 times a Kd for binding of the first binding domain to the antigen in the absence of the immune-stimulatory compound, and
- iii) a Kd for binding of the Fc domain to an Fc receptor in the presence of the immune-stimulatory compound is no greater than about 100 times a Kd for binding of the Fc domain to the Fc receptor in the absence of the immune-stimulatory compound;
- and
- c) a linker attaching the antibody construct to the immune-stimulatory compound, wherein the linker is covalently bound to the antibody construct and the linker is covalently bound to the immune-stimulatory compound, and wherein a molar ratio of immune-stimulatory compound to antibody construct is less than 8;
- and
- wherein immune cell activation caused by the conjugate when bound to the tumor antigen as measured by a cytokine release assay is greater than immune cell activation is greater than immune cell activation in the absence of binding to the tumor antigen.
6 more elements
A conjugate for use in activating an immune cell comprising:
- a) an immune-stimulatory compound;
- b) an antibody construct comprising a first binding domain and an Fc domain, wherein the first binding domain comprises a variable region comprising a set of CDR sequences that comprises at least 80% sequence identity to a set of variable region CDR sequences set forth in TABLE 3 or TABLE 11;
- c) a linker attaching the antibody construct to the immune-stimulatory compound, wherein the linker is covalently bound to the antibody construct and the linker is covalently bound to the immune-stimulatory compound, and wherein a molar ratio of immune-stimulatory compound to antibody construct is less than 8;
- and
- wherein immune cell activation caused by the conjugate when bound to the tumor antigen as measured by a cytokine release assay is greater than immune cell activation is greater than immune cell activation in the absence of binding to the tumor antigen.
2 more elements
A conjugate for use in activating an immune cell comprising:
- a) an immune-stimulatory compound;
- b) an antibody construct comprising a first binding domain and an Fc domain, wherein:
- i) the first binding domain comprises a variable region comprising a set of CDR sequences that comprises at least 80% sequence identity to a set of variable region CDR sequences set forth in TABLE 3 or TABLE 11;
- ii) a Kd for binding of the first binding domain to the antigen in a presence of the immune-stimulatory compound is less than about 100 nM and no greater than about 100 times a Kd for binding of the first binding domain to the antigen in the absence of the immune-stimulatory compound, and
- iii) a Kd for binding of the Fc domain to an Fc receptor in the presence of the immune-stimulatory compound is no greater than about 100 times a Kd for binding of the Fc domain to the Fc receptor in the absence of the immune stimulatory compound;
- and
- c) a linker attaching the antibody construct to the immune-stimulatory compound, wherein the linker is covalently bound to the antibody construct and the linker is covalently bound to the immune-stimulatory compound, and wherein a molar ratio of immune-stimulatory compound to antibody construct is less than 8;
- and
- wherein immune cell activation caused by the conjugate when bound to the tumor antigen as measured by a cytokine release assay is greater than immune cell activation is greater than immune cell activation in the absence of binding to the tumor antigen.
6 more elements
Dependencies are inferred from the claim text.