Methods for predicting cancer drug responsiveness
AssigneeEutropics Pharmaceuticals, Inc.
InventorMichael CARDONE
Life of this patent
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Abstract
The present disclosure relates to compositions and methods of determining cancer cell sensitivity to treatment using antibodies that detect heterodimers comprising Bcl-2 proteins. The disclosure also provides methods for predicting a cancer patient's sensitivity to the cancer treatment.
Claims100
A method for predicting a patient's sensitivity to a cancer treatment, comprising:
- (a) contacting a sample with an antibody or antibody format that recognizes a heterodimer comprising two B-cell lymphoma 2 (BCL-2) proteins, the sample being a specimen from a solid tumor of the patient;
- (b) detecting a signal that indicates the amount of the heterodimer;
- and
- (c) determining a ratio of the amount of heterodimer present in the sample from step (b) to a reference value,
- wherein the reference value comprises the amount of one of the BCL-2 protein monomers of the heterodimer in the sample,
- the ratio being predictive of the patient's sensitivity to the cancer treatment.
A method for predicting a patient's sensitivity to a cancer treatment, comprising:
- (a) contacting a sample with an antibody or antibody format that recognizes a heterodimer comprising two B-cell lymphoma 2 (BCL-2) proteins and an antibody or antibody format that recognizes one of the BCL-2 protein monomers of the heterodimer, the sample being a specimen from a solid tumor of the patient;
- (b) detecting a signal that indicates the amount of the heterodimer and a signal that indicates the amount of the monomer;
- and
- (c) determining a ratio based on the amount heterodimer to the amount of the monomer, the ratio being predictive of the patient's sensitivity to the cancer treatment.
A method for predicting a patient's responsiveness to a checkpoint inhibitor in a sample, comprising measuring the amount of an antibody comprising a Mcl-1/Bim or a BCLXL/Bim heterodimer, wherein the sample comprises an infiltrating lymphocyte population from a solid tumor.
A composition comprising an antibody or antibody format comprising:
- (i) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence is GHTFTEHYIN (SEQ ID NO:
- 1), the heavy chain CDR2 sequence is WIFPGSGSTYYNEKFKG (SEQ ID NO:
- 2);
- and the heavy chain CDR3 sequence is SYSNFWFAY (SEQ ID NO:
- 3);
- and (ii) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence is RASQSIGTSIH (SEQ ID NO:
- 4), the light chain CDR2 sequence is KYASESIS (SEQ ID NO:
- 5), and the light chain CDR3 sequence is QQSNSWPTT (SEQ ID NO:
- 6).
A method of generating a heterodimer antibody, comprising:
- (a) immunizing a subject with a heterodimer induced conformation antigen;
- (b) isolating from the subject a splenic B cell producing the IgG recognizing the heterodimer induced antigen;
- (c) passing the splenic B cell onto a magnetic column for negative selection, wherein the magnetic column for negative selection is coated with a recombinant fusion protein containing one monomer of the heterodimer;
- (d) collecting the flow through of the splenic B cells from the magnetic column for negative selection, and passing the flow through onto a magnetic column for positive selection;
- wherein the magnetic column for positive selection is coated with the heterodimer antigen;
- (e) eluting and collecting the splenic B cells bound to the magnetic column for positive selection;
- (f) culturing the collected cells in a B-cell media;
- and
- (g) isolating the heterodimer specific antibody from the cultured cells, thereby generating a heterodimer antibody.
Dependencies are inferred from the claim text.