Claims for Patent: 7,858,300

Summary for Patent: 7,858,300

Title:	Methods and compositions to evaluate antibody treatment response
Abstract:	The present invention relates to methods and compositions to evaluate or assess the response of a subject to particular therapeutic treatment. More particularly, the invention provides methods to determine the response of subjects, or to adapt the treatment protocol of subjects treated with therapeutic antibodies. The invention is based on a determination of the FCGR3A genotype of a subject. The invention can be used for patients with malignancies, particularly lymphoma, and is suited to select best responders and/or adjust treatment condition or protocol for low responders.
Inventor(s):	Watier; Herve (Ballan-Mire, FR), Cartron; Guillaume (Savonnieres, FR), Colombat; Philippe (Larcay, FR)
Assignee:	Centre Hospitalier Regional et Universitaire de Tours (Cedex Tours, FR)
Application Number:	10/492,183
Patent Claims:	1. A method of predicting the responsiveness of a human follicular CD20 positive non-Hodgkin's lymphoma (NHL) patient to treatment with rituximab comprising: a) determining the identity of an amino acid residue at position 158 of the mature Fc.gamma.RIIIa receptor of said human follicular CD20 positive non-Hodgkin's lymphoma (NHL) patient comprising obtaining a biological sample from a human follicular CD20 positive NHL patient and isolating and sequencing Fc.gamma.RIIIa receptor polypeptides, or portions thereof containing an amino acid residue at position 158 of the mature form of the Fc.gamma.RIIIa receptor from said biological sample to determine the amino acid residue at position 158 of said Fc.gamma.RIIIa receptor polypeptides, or contacting antibody reagents specific for each allele of the Fc.gamma.RIIIa receptor with said biological sample to determine the amino acid residue at position 158 present of said Fc.gamma.RIIIa receptor; and b) identifying the amino acid residue at position 158 of the mature Fc.gamma.RIIIa receptor as a valine (V) or phenylalanine (F), the presence of a homozygous (V/V) at position 158 of the Fc.gamma.RIIIa receptor polypeptide being predictive of better responsiveness of said patient to treatment of follicular CD20 positive NHL with rituximab and the presence of a heterozygous (F/V) or a homozygous (F/F) at position 158 being predictive of a lower responsiveness of said patient to the treatment of follicular CD20 positive NHL with rituximab. 2. The method according to claim 1, wherein said determining the identity of an amino acid residue at position 158 of the mature Fc.gamma.RIIIa receptor comprises sequencing Fc.gamma.RIIIa receptor polypeptides or portions thereof comprising the amino acid residue at position 158 of the mature form of the Fc.gamma.RIIIa receptor. 3. The method according to claim 1, wherein said determining the identity of an amino acid residue at position 158 of the mature Fc.gamma.RIIIa receptor comprises contacting antibody reagents specific for each allele of the Fc.gamma.RIIIa receptor with said biological sample to determine the amino acid residue at position 158 of the Fc.gamma.RIIIa receptor present in said biological sample obtained from said patient. 4. A method of selecting a human patient that is more likely to respond to treatment of follicular CD20 positive non-Hodgkin's lymphoma (NHL) with rituximab comprising: a) identifying the amino acid at position 158 of the mature Fc.gamma.RIIIa receptor comprising obtaining a biological sample from said human patient and sequencing Fc.gamma.RIIIa receptor polypeptides, or portions thereof containing an amino acid residue at position 158 of the mature form of the Fc.gamma.RIIIa receptor from said biological sample or contacting antibody reagents specific for each allele of the Fc.gamma.RIIIa receptor with said biological sample to determine the amino acid residue at position 158 present in said biological sample obtained from said human patient; and b) selecting a human patient that is homozygous for (V/V) at position 158 of the mature form of the Fc.gamma.RIIIa receptor polypeptide as being a patient that is more likely to respond to treatment of follicular CD20 positive non-Hodgkin's lymphoma (NHL) with rituximab than a human patient that is heterozygous (F/V) or homozygous (F/F) at position 158 of the mature form of the Fc.gamma.RIIIa receptor polypeptide. 5. The method according to claim 4, wherein said identifying the amino acid at position 158 of the mature Fc.gamma.RIIIa receptor comprises sequencing Fc.gamma.RIIIa receptor polypeptides or portions thereof comprising the amino acid residue at position 158 of the mature form of the Fc.gamma.RIIIa receptor. 6. The method according to claim 4, wherein said identifying the amino acid at position 158 of the mature Fc.gamma.RIIIa receptor comprises contacting antibody reagents specific for each allele of the Fc.gamma.RIIIa receptor with said biological sample to determine the amino acid residue at position 158 present in the biological sample obtained from said human patient. 7. A method of predicting the responsiveness of a human follicular CD20 positive non-Hodgkin's lymphoma (NHL) patient to treatment with rituximab comprising: a) determining the identity of an amino acid residue at position 158 of the mature Fc.gamma.RIIIa receptor of said human follicular CD20 positive non-Hodgkin's lymphoma (NHL) patient comprising obtaining a biological sample from a human follicular CD20 positive NHL patient and carrying out a method selected from the group consisting of: (i) isolating and sequencing the gene of the human patient that encodes the Fc.gamma.RIIIa receptor, or a portion of the gene that encodes an amino acid at position 158 of the mature form of the Fc.gamma.RIIIa receptor in said biological sample, to determine the identity of the amino acid residue at position 158 of the mature Fc.gamma.RIIIa receptor; ii) isolating and hybridizing Fc.gamma.RIIIa receptor encoding RNA or a portion thereof in said biological sample, said portion comprising those nucleotides encoding amino acid residue 158 of the mature form of the Fc.gamma.RIIIa receptor, with a nucleic acid probe specific for the nucleotides encoding valine or phenylalanine to determine the amino acid residue present at position 158 of the mature Fc.gamma.RIIIa receptor; (iii) A) obtaining genomic DNA from said biological sample; B) amplifying the Fc.gamma.RIIIa receptor gene or a portion thereof in said biological sample to form amplification products comprising the nucleotides encoding the amino acid residue at position 158 of the mature form of the Fc.gamma.RIIIa receptor; and C) sequencing the amplification products of step B) and determining the identity of the amino acid residue at position 158 of said mature form of the Fc.gamma.RIIIa receptor; and (iv) A) obtaining genomic DNA from said biological sample; B) amplifying the Fc.gamma.RIIIa receptor gene or a portion thereof in said biological sample to form amplification products comprising nucleotides encoding the amino acid at position 158 of the mature form of the Fc.gamma.RIIIa receptor; C) digesting the amplification products of step B) with an enzyme that cleaves at a valine codon to form digestion products; and D) analyzing the digestion products of step C) to identify the presence of digestion products indicative of the presence of a valine at position 158 of the mature form of the Fc.gamma.RIIIa receptor; and b) the presence of a homozygous valine at position 158 of the mature Fc.gamma.RIIIa receptor encoded in the genomic DNA from said biological sample or the presence of a nucleotide sequence encoding a valine at position 158 of the mature Fc.gamma.RIIIa receptor in RNA from said biological sample being predictive of better responsiveness of said patient to treatment of follicular CD20 positive NHL with rituximab in comparison to a human patient that is homozygous (F/F) at position 158 of the mature form of the Fc.gamma.RIIIa receptor. 8. The method according to claim 7, wherein said determining the identity of an amino acid residue at position 158 of the mature Fc.gamma.RIIIa receptor comprises: a) obtaining genomic DNA from said biological sample; b) amplifying the Fc.gamma.RIIIa receptor gene or a portion thereof in said biological sample to form amplification products comprising nucleotides encoding the amino acid residue at position 158 of the mature form of the Fc.gamma.RIIIa receptor; and c) sequencing the amplification products of step b) and determining the identity of the amino acid residue at position 158 of said Fc.gamma.RIIIa receptor. 9. The method according to claim 7, wherein said determining the identity of an amino acid residue at position 158 of the mature Fc.gamma.RIIIa receptor comprises: a) obtaining genomic DNA from said biological sample; b) amplifying the Fc.gamma.RIIIa receptor gene or a portion thereof in said biological sample to form amplification products comprising nucleotides encoding the amino acid at position 158 of the mature form of the Fc.gamma.RIIIa receptor; c) digesting the amplification products of step b) with an enzyme that cleaves at a valine codon to form digestion products; and d) analyzing the digestion products of step c) to identify the presence of digestion products indicative of the presence of valine at position 158 of the mature form of the Fc.gamma.RIIIa receptor. 10. The method according to claim 8, wherein said amplifying is performed by polymerase chain reaction (PCR), RT-PCR or nested PCR. 11. The method according to claim 9, wherein said amplifying is performed by polymerase chain reaction (PCR), RT-PCR or nested PCR. 12. The method according to claim 10, wherein said amplifying is performed by nested PCR and primers comprising SEQ ID NOs: 1, 2, 3 and 4 are used in said nested PCR process. 13. The method according to claim 11, wherein said amplifying is performed by nested PCR and primers comprising SEQ ID NOs: 1, 2, 3 and 4 are used in said nested PCR process. 14. The method according to claim 7, wherein said determining the identity of an amino acid residue at position 158 of the mature Fc.gamma.RIIIa receptor comprises hybridization of the Fc.gamma.RIIIa receptor encoding RNA or a portion thereof in said biological sample, said portion comprising those nucleotides encoding amino acid residue 158 of the mature form of the Fc.gamma.RIIIa receptor, with a nucleic acid probe specific for the nucleotides encoding valine or phenylalanine. 15. A method of selecting a human patient that is more likely to respond to treatment of follicular CD20 positive non-Hodgkin's lymphoma (NHL) with rituximab comprising: a) determining the identity of an amino acid residue at position 158 of the mature Fc.gamma.RIIIa receptor of a human patient comprising a method selected from the group consisting of: (i) obtaining a biological sample from said human patient containing genomic DNA and sequencing the gene of the human patient that encodes the Fc.gamma.RIIIa receptor, or a portion of the gene that encodes an amino acid at position 158 of the mature form of the Fc.gamma.RIIIa receptor, to determine the identity of the amino acid residue at position 158 of the mature Fc.gamma.RIIIa receptor; (ii) hybridizing the Fc.gamma.RIIIa receptor encoding RNA or a portion thereof present in a biological sample from said human patient, said portion comprising those nucleotides encoding amino acid residue 158 of the mature form of the Fc.gamma.RIIIa receptor, with a nucleic acid probe specific for the nucleotides encoding valine or phenylalanine; (iii) A) obtaining genomic DNA from a biological sample from said human patient; B) amplifying the Fc.gamma.RIIIa receptor gene or a portion thereof in said biological sample to form amplification products comprising the nucleotides encoding the amino acid residue at position 158 of the mature form of the Fc.gamma.RIIIa receptor; and C) sequencing the amplification products of step B) and determining the identity of the amino acid residue at position 158 of said Fc.gamma.RIIIa receptor; and (iv) A) obtaining genomic DNA from a biological sample of said human patient; B) amplifying the Fc.gamma.RIIIa receptor gene or a portion thereof in said biological sample to form amplification products comprising nucleotides encoding the amino acid at position 158 of the mature form of the Fc.gamma.RIIIa receptor; C) digesting the amplification products of step B) with an enzyme that cleaves at a valine codon to form digestion products; and D) analyzing the digestion products of step C) for the presence of digestion products indicative of the presence of a valine at position 158 of the Fc.gamma.RIIIa receptor; and b) selecting a human patient that has a valine at position 158 of the mature form of the Fc.gamma.RIIIa receptor encoded in the genomic DNA from said biological sample or in the nucleotide sequence of the RNA encoding the mature form of the Fc.gamma.RIIIa receptor polypeptide present in said biological sample as being more likely to respond to treatment of follicular CD20 positive non-Hodgkin's lymphoma (NHL) with rituximab than a human patient without said valine. 16. The method according to claim 15, wherein said determining the identity of an amino acid residue at position 158 of the mature Fc.gamma.RIIIa receptor comprises: a) obtaining genomic DNA from said biological sample; b) amplifying the Fc.gamma.RIIIa receptor gene or a portion thereof in said biological sample to form amplification products comprising the nucleotides encoding the amino acid residue at position 158 of the mature form of the Fc.gamma.RIIIa receptor; and c) sequencing the amplification products of step b) and determining the identity of the amino acid residue at position 158 of said Fc.gamma.RIIIa receptor. 17. The method according to claim 15, wherein said determining the identity of an amino acid residue at position 158 of the mature Fc.gamma.RIIIa receptor comprises: a) obtaining genomic DNA from said biological sample; b) amplifying the Fc.gamma.RIIIa receptor gene or a portion thereof in said biological sample to form amplification products comprising nucleotides encoding the amino acid at position 158 of the mature form of the Fc.gamma.RIIIa receptor; c) digesting the amplification products of step b) with an enzyme specific for a restriction site to form digestion products; and d) analyzing the digestion products of step c) for the presence of digestion products indicative of the presence of a valine at position 158 of the Fc.gamma.RIIIa receptor. 18. The method according to claim 16, wherein said amplifying is performed by polymerase chain reaction (PCR), RT-PCR or nested PCR. 19. The method according to claim 17, wherein said amplifying is performed by polymerase chain reaction (PCR), RT-PCR or nested PCR. 20. The method according to claim 18, wherein said amplifying is performed by nested PCR and primers comprising SEQ ID NOs: 1, 2, 3 and 4 are used in said nested PCR process. 21. The method according to claim 19, wherein said amplifying is performed by nested PCR and primers comprising at least one of SEQ ID NOs: 1, 2, 3 and 4 are used in said nested PCR process. 22. The method according to claim 15, wherein said determining the identity of an amino acid residue at position 158 of the mature Fc.gamma.RIIIa receptor comprises hybridization of the Fc.gamma.RIIIa receptor encoding RNA or a portion thereof present in a biological sample from said human patient, said portion comprising those nucleotides encoding amino acid residue 158 of the mature form of the Fc.gamma.RIIIa receptor, with a nucleic acid probe specific for the nucleotides encoding valine or phenylalanine. 23. A method of predicting the responsiveness of a human subject having follicular CD20 positive non-Hodgkins lymphoma (NHL) to treatment with rituximab, comprising: a) identifying the amino acid at position 158 of the mature Fc.gamma.RIIIa receptor in a biological sample from a human subject having follicular CD20 positive NHL patient as a valine (V) or a phenylalanine (F); and b) predicting better responsiveness of the human subject to treatment with rituximab based on the identification of the human subject having a homozygous (V/V) at position 158 of the Fc.gamma.RIIIa receptor, or predicting lower responsiveness of the human subject to treatment with rituximab based on the identification of the human subject having a heterozygous (F/V) or a homozygous (F/F) at position 158 of the Fc.gamma.RIIIa receptor. 24. A method for treating a human patient with follicular CD20 positive non-Hodgkin's lymphoma (NHL) that is more likely to respond to treatment with rituximab comprising: administering rituximab to a human subject identified as being homozygous for valine (V/V) at position 158 of the mature form of the Fc.gamma.RIIIa receptor, such that the human subject is more likely to respond to treatment with rituximab as compared to a human subject identified as being heterozygous for valine (FN) or homozygous for phenylalanine (F/F) at position 158 of the mature form of the Fc.gamma.RIIIa receptor.

Details for Patent 7,858,300

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2021-10-19
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2021-10-19
Genentech, Inc.	RITUXAN HYCELA	rituximab and hyaluronidase human	Injection	761064	06/22/2017		2021-10-19