US 11,896,643 B2Granted

Fibroblast binding agents and use thereof

AssigneeOrionis Biosciences BV

InventorsNikolai Kley, Jan Tavernier, Anje Cauwels

Life of this patent

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Abstract

The present invention relates, in part, to agents that bind fibroblast activation protein (FAP) and their use as diagnostic and therapeutic agents. The present invention further relates to pharmaceutical compositions comprising the FAP binding agents and their use in the treatment of various diseases.

Claims11

Dependent claims

A chimeric protein comprising:

(a) at least one recombinant heavy-chain-only antibody (VHH) or a single-chain antibody (scFv) targeting moiety that is a fibroblast activation protein (FAP) binding agent, wherein the FAP binding agent comprises three complementarity determining regions (CDR1, CDR2, and CDR3), wherein:
CDR1 comprises the amino acid sequence of SEQ ID NO:
95;
CDR2 comprises the amino acid sequence of SEQ ID NO:
121;
CDR3 comprises the amino acid sequence of SEQ ID NO:
152;
CDR1 comprises the amino acid sequence of SEQ ID NO:
87;
CDR2 comprises the amino acid sequence of SEQ ID NO:
116;
CDR3 comprises the amino acid sequence of SEQ ID NO:
145;
CDR1 comprises the amino acid sequence of SEQ ID NO:
89;
CDR2 comprises the amino acid sequence of SEQ ID NO:
117;
CDR3 comprises the amino acid sequence of SEQ ID NO:
146;
CDR1 comprises the amino acid sequence of SEQ ID NO:
90;
CDR2 comprises the amino acid sequence of SEQ ID NO:
117;
CDR3 comprises the amino acid sequence of SEQ ID NO:
147;
CDR1 comprises the amino acid sequence of SEQ ID NO:
91;
CDR2 comprises the amino acid sequence of SEQ ID NO:
118;
CDR3 comprises the amino acid sequence of SEQ ID NO:
148;
CDR1 comprises the amino acid sequence of SEQ ID NO:
92;
CDR2 comprises the amino acid sequence of SEQ ID NO:
118;
CDR3 comprises the amino acid sequence of SEQ ID NO:
149;
CDR1 comprises the amino acid sequence of SEQ ID NO:
93;
CDR2 comprises the amino acid sequence of SEQ ID NO:
119;
CDR3 comprises the amino acid sequence of SEQ ID NO:
146;
CDR1 comprises the amino acid sequence of SEQ ID NO:
94;
CDR2 comprises the amino acid sequence of SEQ ID NO:
120;
CDR3 comprises the amino acid sequence of SEQ ID NO:
150;
CDR1 comprises the amino acid sequence of SEQ ID NO:
94;
CDR2 comprises the amino acid sequence of SEQ ID NO:
120;
CDR3 comprises the amino acid sequence of SEQ ID NO:
151;
CDR1 comprises the amino acid sequence of SEQ ID NO:
96;
CDR2 comprises the amino acid sequence of SEQ ID NO:
122;
CDR3 comprises the amino acid sequence of SEQ ID NO:
153;
CDR1 comprises the amino acid sequence of SEQ ID NO:
97;
CDR2 comprises the amino acid sequence of SEQ ID NO:
123;
CDR3 comprises the amino acid sequence of SEQ ID NO:
154;
CDR1 comprises the amino acid sequence of SEQ ID NO:
98;
CDR2 comprises the amino acid sequence of SEQ ID NO:
124;
CDR3 comprises the amino acid sequence of SEQ ID NO:155;
CDR1 comprises the amino acid sequence of SEQ ID NO:
99;
CDR2 comprises the amino acid sequence of SEQ ID NO:
125;
CDR3 comprises the amino acid sequence of SEQ ID NO:
156;
CDR1 comprises the amino acid sequence of SEQ ID NO:
100;
CDR2 comprises the amino acid sequence of SEQ ID NO:
126;
CDR3 comprises the amino acid sequence of SEQ ID NO:
157;
CDR1 comprises the amino acid sequence of SEQ ID NO:
101;
CDR2 comprises the amino acid sequence of SEQ ID NO:
127;
CDR3 comprises the amino acid sequence of SEQ ID NO:
158;
CDR1 comprises the amino acid sequence of SEQ ID NO:
102;
CDR2 comprises the amino acid sequence of SEQ ID NO:
128;
CDR3 comprises the amino acid sequence of SEQ ID NO:
159;
CDR1 comprises the amino acid sequence of SEQ ID NO:
103;
CDR2 comprises the amino acid sequence of SEQ ID NO:
129;
CDR3 comprises the amino acid sequence of SEQ ID NO:
160;
CDR1 comprises the amino acid sequence of SEQ ID NO:
104;
CDR2 comprises the amino acid sequence of SEQ ID NO:
129;
CDR3 comprises the amino acid sequence of SEQ ID NO:
160;
CDR1 comprises the amino acid sequence of SEQ ID NO:
105;
CDR2 comprises the amino acid sequence of SEQ ID NO:
130;
CDR3 comprises the amino acid sequence of SEQ ID NO:
160;
CDR1 comprises the amino acid sequence of SEQ ID NO:
105;
CDR2 comprises the amino acid sequence of SEQ ID NO:
131;
CDR3 comprises the amino acid sequence of SEQ ID NO:
161;
CDR1 comprises the amino acid sequence of SEQ ID NO:
106;
CDR2 comprises the amino acid sequence of SEQ ID NO:
132;
CDR3 comprises the amino acid sequence of SEQ ID NO:
162;
CDR1 comprises the amino acid sequence of SEQ ID NO:
106;
CDR2 comprises the amino acid sequence of SEQ ID NO:
132;
CDR3 comprises the amino acid sequence of SEQ ID NO:
162;
CDR1 comprises the amino acid sequence of SEQ ID NO:
107;
CDR2 comprises the amino acid sequence of SEQ ID NO:
133;
CDR3 comprises the amino acid sequence of SEQ ID NO:
163;
CDR1 comprises the amino acid sequence of SEQ ID NO:
108;
CDR2 comprises the amino acid sequence of SEQ ID NO:
132;
CDR3 comprises the amino acid sequence of SEQ ID NO:
164;
CDR1 comprises the amino acid sequence of SEQ ID NO:
106;
CDR2 comprises the amino acid sequence of SEQ ID NO:
134;
CDR3 comprises the amino acid sequence of SEQ ID NO:
165;
CDR1 comprises the amino acid sequence of SEQ ID NO:
106;
CDR2 comprises the amino acid sequence of SEQ ID NO:
134;
CDR3 comprises the amino acid sequence of SEQ ID NO:
165;
CDR1 comprises the amino acid sequence of SEQ ID NO:
106;
CDR2 comprises the amino acid sequence of SEQ ID NO:
135;
CDR3 comprises the amino acid sequence of SEQ ID NO:
166;
CDR1 comprises the amino acid sequence of SEQ ID NO:
106;
CDR2 comprises the amino acid sequence of SEQ ID NO:
135;
CDR3 comprises the amino acid sequence of SEQ ID NO:
166;
CDR1 comprises the amino acid sequence of SEQ ID NO:
106;
CDR2 comprises the amino acid sequence of SEQ ID NO:
136;
CDR3 comprises the amino acid sequence of SEQ ID NO:
167;
CDR1 comprises the amino acid sequence of SEQ ID NO:
109;
CDR2 comprises the amino acid sequence of SEQ ID NO:
137;
CDR3 comprises the amino acid sequence of SEQ ID NO:
168;
CDR1 comprises the amino acid sequence of SEQ ID NO:
106;
CDR2 comprises the amino acid sequence of SEQ ID NO:
138;
CDR3 comprises the amino acid sequence of SEQ ID NO:
169;
CDR1 comprises the amino acid sequence of SEQ ID NO:
110;
CDR2 comprises the amino acid sequence of SEQ ID NO:
139;
CDR3 comprises the amino acid sequence of SEQ ID NO:
170;
CDR1 comprises the amino acid sequence of SEQ ID NO:
111;
CDR2 comprises the amino acid sequence of SEQ ID NO:
140;
CDR3 comprises the amino acid sequence of SEQ ID NO:
171;
CDR1 comprises the amino acid sequence of SEQ ID NO:
112;
CDR2 comprises the amino acid sequence of SEQ ID NO:
141;
CDR3 comprises the amino acid sequence of SEQ ID NO:
172;
CDR1 comprises the amino acid sequence of SEQ ID NO:
113;
CDR2 comprises the amino acid sequence of SEQ ID NO:
142;
CDR3 comprises the amino acid sequence of SEQ ID NO:
173;
CDR1 comprises the amino acid sequence of SEQ ID NO:
114;
CDR2 comprises the amino acid sequence of SEQ ID NO:
143;
CDR3 comprises the amino acid sequence of SEQ ID NO:
174;
or
CDR1 comprises the amino acid sequence of SEQ ID NO:
115;
CDR2 comprises the amino acid sequence of SEQ ID NO:
144;
CDR3 comprises the amino acid sequence of SEQ ID NO:
175, and
(b) a modified human interferon alpha 2 (IFNα2) signaling agent comprising an amino acid sequence having at least 98% identity with SEQ ID NO:
176 or 177 and having R149A mutation, relative to SEQ ID NO:
176 or 177, that confers reduced affinity or activity for its receptor, as compared to a wild type human IFNα2 having an amino acid sequence of SEQ ID NO:
176 or 177.

224 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/967,288Filed 5 Feb 2019 · us provisional application
Priority: 5 Feb 2018
Published: US 2021/0023167 A128 Jan 2021
Granted: 13 Feb 2024
Term ends: Not estimatedThe source records don’t support an estimate.

Classification28 codes

A61K 38/16
Medicinal preparations containing peptides: peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
A61K 39/395
Medicinal preparations containing antigens or antibodies: antibodies ; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
A61K 31/704
Attached to a carbocyclic compound, e.g. phloridzin: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin,…
A61K 33/24
Medicinal preparations containing inorganic active ingredients: heavy metals; Compounds thereof

Family

Application62/626,453Us provisional application · filed 5 Feb 2018
US 2021/0023167 A1Pre-grant publication · published 28 Jan 2021
US 11,896,643 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A chimeric protein comprising:

(a) at least one recombinant heavy-chain-only antibody (VHH) or a single-chain antibody (scFv) targeting moiety that is a fibroblast activation protein (FAP) binding agent, wherein the FAP binding agent comprises three complementarity determining regions (CDR1, CDR2, and CDR3), wherein:
CDR1 comprises the amino acid sequence of SEQ ID NO:
95;
CDR2 comprises the amino acid sequence of SEQ ID NO:
121;
CDR3 comprises the amino acid sequence of SEQ ID NO:
152;
CDR1 comprises the amino acid sequence of SEQ ID NO:
87;
CDR2 comprises the amino acid sequence of SEQ ID NO:
116;
CDR3 comprises the amino acid sequence of SEQ ID NO:
145;
CDR1 comprises the amino acid sequence of SEQ ID NO:
89;
CDR2 comprises the amino acid sequence of SEQ ID NO:
117;
CDR3 comprises the amino acid sequence of SEQ ID NO:
146;
CDR1 comprises the amino acid sequence of SEQ ID NO:
90;
CDR2 comprises the amino acid sequence of SEQ ID NO:
117;
CDR3 comprises the amino acid sequence of SEQ ID NO:
147;
CDR1 comprises the amino acid sequence of SEQ ID NO:
91;
CDR2 comprises the amino acid sequence of SEQ ID NO:
118;
CDR3 comprises the amino acid sequence of SEQ ID NO:
148;
CDR1 comprises the amino acid sequence of SEQ ID NO:
92;
CDR2 comprises the amino acid sequence of SEQ ID NO:
118;
CDR3 comprises the amino acid sequence of SEQ ID NO:
149;
CDR1 comprises the amino acid sequence of SEQ ID NO:
93;
CDR2 comprises the amino acid sequence of SEQ ID NO:
119;
CDR3 comprises the amino acid sequence of SEQ ID NO:
146;
CDR1 comprises the amino acid sequence of SEQ ID NO:
94;
CDR2 comprises the amino acid sequence of SEQ ID NO:
120;
CDR3 comprises the amino acid sequence of SEQ ID NO:
150;
CDR1 comprises the amino acid sequence of SEQ ID NO:
94;
CDR2 comprises the amino acid sequence of SEQ ID NO:
120;
CDR3 comprises the amino acid sequence of SEQ ID NO:
151;
CDR1 comprises the amino acid sequence of SEQ ID NO:
96;
CDR2 comprises the amino acid sequence of SEQ ID NO:
122;
CDR3 comprises the amino acid sequence of SEQ ID NO:
153;
CDR1 comprises the amino acid sequence of SEQ ID NO:
97;
CDR2 comprises the amino acid sequence of SEQ ID NO:
123;
CDR3 comprises the amino acid sequence of SEQ ID NO:
154;
CDR1 comprises the amino acid sequence of SEQ ID NO:
98;
CDR2 comprises the amino acid sequence of SEQ ID NO:
124;
CDR3 comprises the amino acid sequence of SEQ ID NO:155;
CDR1 comprises the amino acid sequence of SEQ ID NO:
99;
CDR2 comprises the amino acid sequence of SEQ ID NO:
125;
CDR3 comprises the amino acid sequence of SEQ ID NO:
156;
CDR1 comprises the amino acid sequence of SEQ ID NO:
100;
CDR2 comprises the amino acid sequence of SEQ ID NO:
126;
CDR3 comprises the amino acid sequence of SEQ ID NO:
157;
CDR1 comprises the amino acid sequence of SEQ ID NO:
101;
CDR2 comprises the amino acid sequence of SEQ ID NO:
127;
CDR3 comprises the amino acid sequence of SEQ ID NO:
158;
CDR1 comprises the amino acid sequence of SEQ ID NO:
102;
CDR2 comprises the amino acid sequence of SEQ ID NO:
128;
CDR3 comprises the amino acid sequence of SEQ ID NO:
159;
CDR1 comprises the amino acid sequence of SEQ ID NO:
103;
CDR2 comprises the amino acid sequence of SEQ ID NO:
129;
CDR3 comprises the amino acid sequence of SEQ ID NO:
160;
CDR1 comprises the amino acid sequence of SEQ ID NO:
104;
CDR2 comprises the amino acid sequence of SEQ ID NO:
129;
CDR3 comprises the amino acid sequence of SEQ ID NO:
160;
CDR1 comprises the amino acid sequence of SEQ ID NO:
105;
CDR2 comprises the amino acid sequence of SEQ ID NO:
130;
CDR3 comprises the amino acid sequence of SEQ ID NO:
160;
CDR1 comprises the amino acid sequence of SEQ ID NO:
105;
CDR2 comprises the amino acid sequence of SEQ ID NO:
131;
CDR3 comprises the amino acid sequence of SEQ ID NO:
161;
CDR1 comprises the amino acid sequence of SEQ ID NO:
106;
CDR2 comprises the amino acid sequence of SEQ ID NO:
132;
CDR3 comprises the amino acid sequence of SEQ ID NO:
162;
CDR1 comprises the amino acid sequence of SEQ ID NO:
106;
CDR2 comprises the amino acid sequence of SEQ ID NO:
132;
CDR3 comprises the amino acid sequence of SEQ ID NO:
162;
CDR1 comprises the amino acid sequence of SEQ ID NO:
107;
CDR2 comprises the amino acid sequence of SEQ ID NO:
133;
CDR3 comprises the amino acid sequence of SEQ ID NO:
163;
CDR1 comprises the amino acid sequence of SEQ ID NO:
108;
CDR2 comprises the amino acid sequence of SEQ ID NO:
132;
CDR3 comprises the amino acid sequence of SEQ ID NO:
164;
CDR1 comprises the amino acid sequence of SEQ ID NO:
106;
CDR2 comprises the amino acid sequence of SEQ ID NO:
134;
CDR3 comprises the amino acid sequence of SEQ ID NO:
165;
CDR1 comprises the amino acid sequence of SEQ ID NO:
106;
CDR2 comprises the amino acid sequence of SEQ ID NO:
134;
CDR3 comprises the amino acid sequence of SEQ ID NO:
165;
CDR1 comprises the amino acid sequence of SEQ ID NO:
106;
CDR2 comprises the amino acid sequence of SEQ ID NO:
135;
CDR3 comprises the amino acid sequence of SEQ ID NO:
166;
CDR1 comprises the amino acid sequence of SEQ ID NO:
106;
CDR2 comprises the amino acid sequence of SEQ ID NO:
135;
CDR3 comprises the amino acid sequence of SEQ ID NO:
166;
CDR1 comprises the amino acid sequence of SEQ ID NO:
106;
CDR2 comprises the amino acid sequence of SEQ ID NO:
136;
CDR3 comprises the amino acid sequence of SEQ ID NO:
167;
CDR1 comprises the amino acid sequence of SEQ ID NO:
109;
CDR2 comprises the amino acid sequence of SEQ ID NO:
137;
CDR3 comprises the amino acid sequence of SEQ ID NO:
168;
CDR1 comprises the amino acid sequence of SEQ ID NO:
106;
CDR2 comprises the amino acid sequence of SEQ ID NO:
138;
CDR3 comprises the amino acid sequence of SEQ ID NO:
169;
CDR1 comprises the amino acid sequence of SEQ ID NO:
110;
CDR2 comprises the amino acid sequence of SEQ ID NO:
139;
CDR3 comprises the amino acid sequence of SEQ ID NO:
170;
CDR1 comprises the amino acid sequence of SEQ ID NO:
111;
CDR2 comprises the amino acid sequence of SEQ ID NO:
140;
CDR3 comprises the amino acid sequence of SEQ ID NO:
171;
CDR1 comprises the amino acid sequence of SEQ ID NO:
112;
CDR2 comprises the amino acid sequence of SEQ ID NO:
141;
CDR3 comprises the amino acid sequence of SEQ ID NO:
172;
CDR1 comprises the amino acid sequence of SEQ ID NO:
113;
CDR2 comprises the amino acid sequence of SEQ ID NO:
142;
CDR3 comprises the amino acid sequence of SEQ ID NO:
173;
CDR1 comprises the amino acid sequence of SEQ ID NO:
114;
CDR2 comprises the amino acid sequence of SEQ ID NO:
143;
CDR3 comprises the amino acid sequence of SEQ ID NO:
174;
or
CDR1 comprises the amino acid sequence of SEQ ID NO:
115;
CDR2 comprises the amino acid sequence of SEQ ID NO:
144;
CDR3 comprises the amino acid sequence of SEQ ID NO:
175, and
(b) a modified human interferon alpha 2 (IFNα2) signaling agent comprising an amino acid sequence having at least 98% identity with SEQ ID NO:
176 or 177 and having R149A mutation, relative to SEQ ID NO:
176 or 177, that confers reduced affinity or activity for its receptor, as compared to a wild type human IFNα2 having an amino acid sequence of SEQ ID NO:
176 or 177.

224 more elements

Facts

Application

16/967,288Filed 5 Feb 2019 · us provisional application

Priority

5 Feb 2018

Published

US 2021/0023167 A128 Jan 2021

Granted

13 Feb 2024

Term ends

Not estimatedThe source records don’t support an estimate.

Classification28 codes

A61K 38/16
Medicinal preparations containing peptides: peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
A61K 39/395
Medicinal preparations containing antigens or antibodies: antibodies ; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
A61K 31/704
Attached to a carbocyclic compound, e.g. phloridzin: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin,…
A61K 33/24
Medicinal preparations containing inorganic active ingredients: heavy metals; Compounds thereof