Anti-CD38 Antibody Sequences for Stroma-Independent Cell Killing
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Solution Overview
Problem
Existing anti-CD38 antibodies are ineffective in inducing apoptosis of CD38+ cells without the presence of stroma cells or stroma-derived cytokines, and lack potency in cytotoxic activities such as ADCC and CDC.
Innovation Solution
Development of novel anti-CD38 antibodies, including murine and humanized versions, that can induce apoptosis, ADCC, and CDC independently of stroma cells or cytokines, with specific sequences and structures optimized for high cytotoxic activity against CD38+ cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing anti-CD38 antibodies are used, then they can bind to CD38 on cell surfaces, but they fail to induce apoptosis without stroma cells or stroma-derived cytokines
Solution Approach 1:
The patent applies parameter changes by modifying the antibody structure and binding characteristics. The novel anti-CD38 antibodies (e.g., 38SB13, 38SB18, 38SB19) have altered amino acid sequences in their variable regions compared to existing antibodies, enabling them to induce apoptosis independently of stroma cells. This structural parameter change resolves the contradiction by making the apoptosis induction capability reliable without requiring stroma cell support.
2Reliability
If existing anti-CD38 antibodies are used, then they show limited cytotoxic activity, but they lack potency in ADCC and CDC mechanisms
Solution Approach 1:
The patent employs parameter changes by optimizing the constant region and Fc portion of the antibodies to enhance their ability to engage immune effectors. The novel antibodies have modified Fc regions that improve complement binding and Fc receptor interaction, thereby significantly enhancing ADCC and CDC potency. This resolves the contradiction by making the cytotoxic activity reliable while eliminating the harmful ineffectiveness in immune-mediated killing mechanisms.
3Reliability
If novel anti-CD38 antibodies with optimized sequences are developed, then high cytotoxic activity and apoptotic potency are achieved, but the complexity of antibody development and characterization increases
Solution Approach 1:
The patent applies segmentation by dividing the antibody development process into distinct modular components: variable region optimization for antigen binding, constant region optimization for effector function, and systematic characterization of individual mechanisms (apoptosis, ADCC, CDC). This modular approach manages the complexity by allowing parallel development and evaluation of different antibody features, thereby achieving high reliability without being overwhelmed by the overall complexity of the development process.
Data Source
AI summary
Antibodies, humanized antibodies, resurfaced antibodies, antibody fragments, derivatized antibodies, and conjugates of same with cytotoxic agents, which specifically bind to CD38, are capable of killing CD38′ cells by apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and/or complement-dependent cytotoxicity (CDC). Said antibodies and fragments thereof may be used in the treatment of tumors that express CD38 protein, such as multiple myeloma, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, or acute lymphocytic leukemia, or the treatment of autoimmune and inflammatory diseases such as systemic lupus, rheumatoid arthritis, multiple sclerosis, erythematosus, and asthma. Said derivatized antibodies may be used in the diagnosis and imaging of tumors that express elevated levels of CD38. Also provided are cytotoxic conjugates comprising a cell binding agent and a cytotoxic agent, therapeutic compositions comprising the conjugate, methods for using the conjugates in the inhibition of cell growth and the treatment of disease, and a kit comprising the cytotoxic conjugate. In particular, the cell binding agent is a monoclonal antibody, and epitope-binding fragments thereof, that recognizes and binds the CD38 protein.