CD38 Antibody Modulating Immune Response for Solid Tumors
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Solution Overview
Problem
Current anti-CD38 antibodies are limited in their ability to effectively target and modulate CD38-expressing cancer cells, particularly in solid tumors where CD38 expression is low, and there is a need for antibodies that combine agonistic or modulating properties with targeted cell killing and pharmaceutical compatibility for cancer treatment.
Innovation Solution
Development of CD38 Modulating Antibody Agents, including antibodies or antigen-binding fragments that specifically bind to human CD38, modulating its activity and enhancing immune cell activation and proliferation, with specific binding affinities and epitope recognition, such as the aCD38-a-309 sequence, to target both effector and suppressive immune cells and tumor cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If anti-CD38 antibodies are used to target CD38-expressing cancer cells, then tumor cell killing activity is improved, but effectiveness is reduced in solid tumors where CD38 expression is low
Solution Approach 1:
The patent describes anti-CD38 antibodies that perform multiple functions: they bind to CD38 on tumor cells to induce killing, simultaneously modulate immune cell activation, and enhance cytokine production. This multi-functionality allows the antibody to be effective even when CD38 expression on tumor cells is low, as the immune modulation effects provide additional anti-tumor mechanisms.
Solution Approach 2:
The antibody acts as an intermediary that bridges tumor cells and immune cells. By binding to CD38 on both tumor cells and immune cells, the antibody facilitates interactions between these cell types, enabling immune cells to recognize and attack tumor cells even when direct CD38-mediated killing is reduced in solid tumors.
2Reliability
If CD38-targeting therapies are developed as antagonists or inhibitors, then CD38 enzymatic activity is blocked, but agonistic activities such as immune cell activation are not achieved
Solution Approach 1:
The patent describes changing the functional parameter of the anti-CD38 antibody from pure antagonism to agonism. The antibody is designed to activate CD38 signaling pathways and induce immune cell activation rather than simply blocking enzymatic activity. This parameter change transforms the therapeutic mechanism from enzyme inhibition to immune stimulation.
Solution Approach 2:
Instead of blocking CD38 activity as with traditional antagonists, the patent employs an agonistic antibody that activates CD38 signaling. This inversion of the therapeutic approach transforms the harmful effect of CD38-mediated immunosuppression into a beneficial immune-activating effect, while still allowing for tumor cell killing through alternative mechanisms.
3Reliability
If monoclonal antibodies are designed for direct killing of CD38-expressing tumor cells, then targeted cell killing is improved, but compatibility with pharmaceutical development is limited
Solution Approach 1:
The patent describes optimizing the antibody's functional parameters to achieve both effective cell killing and pharmaceutical compatibility. This includes engineering the antibody to have appropriate binding affinity, half-life, and immunogenicity characteristics that meet pharmaceutical standards while maintaining potent anti-tumor activity.
Solution Approach 2:
The antibody is designed to perform multiple functions that are all compatible with pharmaceutical development: targeted tumor cell killing through CD38 binding, immune cell activation, cytokine induction, and favorable pharmacokinetic properties. This multi-functionality in a single molecule simplifies pharmaceutical development compared to combination therapies.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
These agents enhance immune cell activation and cytotoxicity against CD38-expressing cells, including tumor cells, with increased binding affinity and functional properties comparable to or exceeding those of reference antibodies like daratumumab, offering improved cancer therapy options, especially for solid and hematological cancers.
Implementation Method 1
anti-CD38 antibodies acting as CD38 agonists... have also been characterized as inducing the mobilization of calcium ions
Implementation Method 2
inducing the mobilization of calcium ions, CD38 shedding, NK cell-mediated cytotoxicity, cytokine secretion
Implementation Method 3
NK cell-mediated cytotoxicity
Implementation Method 4
complement-dependent cytotoxicity
Data Source
AI summary
The present disclosure provides antibody sequences found in antibodies that bind to human CD38. In particular, the present disclosure provides sequences of anti-human CD38 antibodies. Antibodies and antigen-binding portions thereof including such sequences present features compatible with pharmaceutical manufacturing and development can be provided as fully human antibodies (e.g., fully human monoclonal antibodies or antigen-binding fragments) that can be useful for medical methods and compositions, in particular for treating cancer.