Production of T cell retargeting hetero-dimeric immunoglobulins
First Claim
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1. A hetero-dimeric immunoglobulin or fragment thereof, comprising:
- (a) a first polypeptide that binds to Protein A comprising an epitope binding region that binds a first epitope and an immunoglobulin constant region; and
(b) a second polypeptide that does not bind to Protein A comprising an epitope binding region, that binds a second epitope and an immunoglobulin constant region;
wherein the first and second polypeptides comprise an engineered immunoglobulin constant region with a modified CH3 domain having a protein-protein interface, wherein the protein-protein interface of the first polypeptide comprises an amino acid substitution at a position selected from the group consisting of;
3, 5, 7, 20, 22, 26, 27, 79, 81, 84, 84.2, 85.1, 86, 88 and 90 (IMGT®
numbering), and wherein the protein-protein interface of the second polypeptide comprises an amino acid substitution at a position selected from the group consisting of 3, 5, 7, 20, 22, 26, 27, 79, 81, 84, 84.2, 84.4, 85.1, 86, 88 and 90 (IMGT®
numbering);
wherein the epitope binding region of the first polypeptide binds the CD3 protein complex and the epitope binding region of the second polypeptide binds a disease associated antigen or wherein the epitope binding region of the first polypeptide binds a disease associated antigen and the epitope binding region of the second polypeptide binds the CD3 protein complex; and
wherein the epitope binding region that binds the CD3 protein complex comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO;
194, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO;
195 and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO;
196, and a light chain CDR1 comprising the amino acid sequence of SEQ ID NO;
197, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO;
198 and a light chain CDR3 comprising the amino acid sequences of;
SEQ ID NO;
199;
orwherein the epitope binding region that binds the CD3 protein complex comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO;
200, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO;
201 and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO;
202, and a light chain CDR1 comprising the amino acid sequence of SEQ ID NO;
203, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO;
204 and a light chain CDR3 comprising the amino acid sequences of;
SEQ ID NO;
205;
orwherein the epitope binding region that binds the CD3 protein complex comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO;
352, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO;
353 and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO;
354, and a light chain CDR1 comprising the amino acid sequence of SEQ ID NO;
355, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO;
356 and a light chain CDR3 comprising the amino acid sequences of SEQ ID NO;
357.
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Abstract
The present invention describes novel hetero-dimeric immunoglobulins or fragments thereof which bind to CD3 and a disease associated antigen. These hetero-dimeric immunoglobulins have been engineered to promote hetero-dimer formation during expression and can be purified to a high degree using a Protein A differential purification technique.
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Citations
14 Claims
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1. A hetero-dimeric immunoglobulin or fragment thereof, comprising:
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(a) a first polypeptide that binds to Protein A comprising an epitope binding region that binds a first epitope and an immunoglobulin constant region; and (b) a second polypeptide that does not bind to Protein A comprising an epitope binding region, that binds a second epitope and an immunoglobulin constant region; wherein the first and second polypeptides comprise an engineered immunoglobulin constant region with a modified CH3 domain having a protein-protein interface, wherein the protein-protein interface of the first polypeptide comprises an amino acid substitution at a position selected from the group consisting of;
3, 5, 7, 20, 22, 26, 27, 79, 81, 84, 84.2, 85.1, 86, 88 and 90 (IMGT®
numbering), and wherein the protein-protein interface of the second polypeptide comprises an amino acid substitution at a position selected from the group consisting of 3, 5, 7, 20, 22, 26, 27, 79, 81, 84, 84.2, 84.4, 85.1, 86, 88 and 90 (IMGT®
numbering);wherein the epitope binding region of the first polypeptide binds the CD3 protein complex and the epitope binding region of the second polypeptide binds a disease associated antigen or wherein the epitope binding region of the first polypeptide binds a disease associated antigen and the epitope binding region of the second polypeptide binds the CD3 protein complex; and wherein the epitope binding region that binds the CD3 protein complex comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO;
194, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO;
195 and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO;
196, and a light chain CDR1 comprising the amino acid sequence of SEQ ID NO;
197, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO;
198 and a light chain CDR3 comprising the amino acid sequences of;
SEQ ID NO;
199;
orwherein the epitope binding region that binds the CD3 protein complex comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO;
200, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO;
201 and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO;
202, and a light chain CDR1 comprising the amino acid sequence of SEQ ID NO;
203, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO;
204 and a light chain CDR3 comprising the amino acid sequences of;
SEQ ID NO;
205;
orwherein the epitope binding region that binds the CD3 protein complex comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO;
352, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO;
353 and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO;
354, and a light chain CDR1 comprising the amino acid sequence of SEQ ID NO;
355, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO;
356 and a light chain CDR3 comprising the amino acid sequences of SEQ ID NO;
357. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14)
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12. A hetero-dimeric immunoglobulin or fragment thereof that binds to:
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i) the CD3 protein complex and HER2, wherein the first polypeptide has an amino acid sequence of SEQ ID NO;
159 and is assembled with a light chain of amino acid sequence of SEQ ID NO;
47 and binds CD3 epsilon, and wherein the second polypeptide has an amino acid sequence of SEQ ID NO;
160 and binds HER2;ii) the CD3 protein complex and HER2, wherein the first polypeptide has an amino acid sequence of SEQ ID NO;
161 and is assembled with a cognate light chain of amino acid sequence of SEQ ID NO;
3 and binds HER2, and wherein the second polypeptide has an amino acid sequence of SEQ ID NO;
162 and binds CD3 epsilon;iii) the CD3 protein complex and HER2, wherein the first polypeptide has an amino acid sequence of SEQ ID NO;
163 and is assembled with a light chain of amino acid sequence of SEQ ID NO;
47 and binds CD3 epsilon, and wherein the second polypeptide has an amino acid sequence of SEQ ID NO;
164 and binds HER2;iv) the CD3 protein complex and HER2, wherein the first polypeptide has an amino acid sequence of SEQ ID NO;
165 and is assembled with a light chain of amino acid sequence of SEQ ID NO;
166 and binds CD3 epsilon, and wherein the second polypeptide has an amino acid sequence of SEQ ID NO;
167 and binds HER2;v) the CD3 protein complex and HER2, wherein the first polypeptide has an amino acid sequence of SEQ ID NO;
168 and is assembled with a light chain of amino acid sequence of SEQ ID NO;
89 and binds CD3 epsilon, and wherein the second polypeptide has an amino acid sequence of SEQ ID NO;
167 and binds HER2;vi) the CD3 protein complex and CD38, wherein the first polypeptide has an amino acid sequence of SEQ ID NO;
169 and is assembled with a cognate light chain of amino acid sequence of SEQ ID NO;
119 and binds CD38, and wherein the second polypeptide has an amino acid sequence of SEQ ID NO;
162 and binds CD3 epsilon;vii) the CD3 protein complex and CD38, wherein the first polypeptide has an amino acid sequence of SEQ ID NO;
170 and is assembled with a cognate light chain of amino acid sequence of SEQ ID NO;
138 and binds CD38, and wherein the second polypeptide has an amino acid sequence of SEQ ID NO;
171 and binds CD3 epsilon;viii) the CD3 protein complex and CD38, wherein the first polypeptide has an amino acid sequence of SEQ ID NO;
176 and is assembled with a cognate light chain of amino acid sequence of SEQ ID NO;
119 and binds CD38, and wherein the second polypeptide has an amino acid sequence of SEQ ID NO;
177 and binds CD3 epsilon;ix) the CD3 protein complex and CD38, wherein the first polypeptide has an amino acid sequence of SEQ ID NO;
178 and is assembled with a cognate light chain of amino acid sequence of SEQ ID NO;
128 and binds CD38, and wherein the second polypeptide has an amino acid sequence of SEQ ID NO;
179 and binds CD3 epsilon;x) the CD3 protein complex and OX40 wherein the first polypeptide has an amino acid sequence of SEQ ID NO;
172 and is assembled with a cognate light chain of amino acid sequence of SEQ ID NO;
173 and binds OX40, and wherein the second polypeptide has an amino acid sequence of SEQ ID NO;
162 and binds CD3 epsilon;xi) the CD3 protein complex and EGFR wherein the first polypeptide has an amino acid sequence of SEQ ID NO;
174 and is assembled with a cognate light chain of amino acid sequence of SEQ ID NO;
175 and binds EGFR, and wherein the second polypeptide has an amino acid sequence of SEQ ID NO;
171 and binds CD3 epsilon;xii) the CD3 protein complex and CD20, wherein the first polypeptide has an amino acid sequence of SEQ ID NO;
180 and is assembled with a cognate light chain of amino acid sequence of SEQ ID NO;
181 and binds CD20, and wherein the second polypeptide has an amino acid sequence of SEQ ID NO;
177 and binds CD3 epsilon.
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Specification