Monoclonal antibodies, compositions and methods for detecting complement factor D
Inventors
Cummings, William Jason • Freeman, Jeremy A. • Li, Yi • Shaffer, Kathleen A. • Yabuki, Munehisa
Assignees
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Publication Number
US-12129290-B2
Publication Date
2024-10-29
Expiration Date
Abstract
Disclosed herein are monoclonal antibodies that specifically bind to human mature Factor D and that do not bind to human Pro-Factor D, monoclonal antibodies that specifically bind to human Pro-Factor D and do not bind to human mature Factor D, and monoclonal antibodies that bind to both human mature Factor D and human Pro-Factor D. Also disclosed are methods of using the monoclonal antibodies, and compositions comprising the same, for detection of the mature and/or the pro-form of Factor D in biological samples, to determine the status of the Alternative Pathway of Complement (APC) in a mammalian subject, or to determine the status of Factor D after treatment with a MASP-3 inhibitory agent which inhibits the conversion of Pro-Factor D to mature Factor D.
Core Innovation
The invention relates to isolated monoclonal antibodies, or antigen-binding fragments thereof, that specifically bind an epitope on the activation (“Pro”) peptide of human Factor D. The binding domain comprises defined heavy-chain and light-chain complementarity determining regions (CDRs), including HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3, with specified amino acid sequences and position constraints, or alternative CDR selections by SEQ ID numbers.
A related component of the invention is the use of these Pro-Factor D-specific monoclonal antibodies or antigen-binding fragments in in vitro immunoassays to determine the presence or amount of Pro-Factor D in a test sample. The method includes contacting a test sample with the Pro-Factor D-specific monoclonal antibody in an in vitro immunoassay and detecting the antibody bound to Pro-Factor D, with binding indicating the presence or amount of Pro-Factor D in the sample.
The invention further extends to methods for assessing the extent of alternative pathway complement (APC) activation by immunoassay readouts of mature Factor D and Pro-Factor D. The method includes capturing and detecting mature Factor D using antibodies that specifically bind an epitope present in mature Factor D and capturing and detecting Pro-Factor D using Pro-Factor D-specific antibodies that specifically bind the Pro activation peptide epitope present in Pro-Factor D but do not bind mature Factor D, and comparing the detected levels to a predetermined level or control sample.
Additionally, the invention provides methods for monitoring the efficacy of treatment with a MASP-3 inhibitory antibody or antigen-binding fragment in a mammalian subject by assessing Pro-Factor D concentrations in biological samples before and after treatment and comparing the levels. The monitoring immunoassay specifically detects or quantitates Pro-Factor D protein and not mature Factor D protein.
Claims Coverage
The independent claims cover four inventive features: Pro-Factor D epitope-specific antibodies with defined CDR sets, an in vitro immunoassay for determining Pro-Factor D presence or amount, an APC activation assessment method comparing mature Factor D and/or Pro-Factor D levels to control or predetermined levels, and monitoring treatment efficacy of a MASP-3 inhibitory antibody. Across these claims, the main inventive features revolve around epitope selectivity for Pro-Factor D versus mature Factor D and the use of specifically defined CDR sequence sets and epitope characters.
Pro-Factor D epitope-binding antibody with defined six CDR set
An isolated antibody or antigen-binding fragment thereof that specifically binds to an epitope on the activation (“Pro”) peptide of human Factor D, wherein the isolated antibody or antigen-binding fragment thereof comprises a binding domain comprising six CDRs defined either by specified HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 amino-acid sequence patterns with position constraints, or by CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 defined by SEQ ID numbers.
In vitro immunoassay for Pro-Factor D presence or amount using Pro epitope-specific antibody
A method of determining the presence or amount of Pro-Factor D in a test sample, the method comprising contacting a test sample with an anti-human Pro-Factor D-specific monoclonal antibody or antigen-binding fragment thereof, in an in vitro immunoassay, and detecting the presence or amount of the antibody or antigen-binding fragment thereof bound to Pro-Factor D.
APC activation assessment by comparing mature Factor D and/or Pro-Factor D immunoassay detection with controls
A method of assessing the extent of alternative pathway complement (APC) activation in a test sample comprising performing an immunoassay that captures and detects mature Factor D and/or Pro-Factor D and comparing the detected level with a predetermined level or control sample, wherein the level of mature Factor D and/or Pro-Factor D detected is indicative of the extent of alternative pathway complement activation.
Monitoring MASP-3 inhibitory antibody efficacy by immunoassay measurement of Pro-Factor D levels
A method for monitoring the efficacy of treatment with a MASP-3 inhibitory antibody, or antigen-binding fragment thereof, in a mammalian subject comprising assessing Pro-Factor D in a biological sample after a first point in time and after a second point in time, and comparing the levels to determine efficacy using an immunoassay that specifically detects or quantitates Pro-Factor D and not mature-Factor D protein.
Across the independent claims, the patent claim set centers on Pro-Factor D epitope specificity versus mature Factor D using defined antibody CDR sequence sets, and uses these antibodies in immunoassays to quantify Pro-Factor D, assess alternative pathway complement activation, and monitor the efficacy of treatment with a MASP-3 inhibitory antibody.
Stated Advantages
Enables determining the presence or amount of Pro-Factor D in a test sample using an in vitro immunoassay.
Indicates the extent of alternative pathway complement (APC) activation by comparing detected levels of mature Factor D and/or Pro-Factor D to predetermined levels or control samples.
Enables monitoring the efficacy of treatment with a MASP-3 inhibitory antibody by comparing Pro-Factor D concentrations assessed before and after treatment.
Allows immunoassay differentiation to specifically detect or quantitate Pro-Factor D protein and not mature Factor D protein using epitope-specific antibodies.
Documented Applications
Immunoassays for detecting or quantitating Pro-Factor D presence or amount in a test sample.
Assessing the extent of alternative pathway complement (APC) activation in a test sample by comparing immunoassay-detected levels of mature Factor D and/or Pro-Factor D to predetermined levels or control samples.
Monitoring efficacy of treatment with a MASP-3 inhibitory antibody in a mammalian subject by assessing Pro-Factor D concentrations before and after treatment.
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