CD38 Modulating Antibodies for Immune Activation in Solid Tumors
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Solution Overview
Problem
Current anti-CD38 antibodies are limited in their ability to target solid tumors, as CD38 expression is generally lower or absent on tumor cells in these cancers, and existing therapies may not effectively combine CD38-specific agonistic or modulating properties with targeted cell killing or activation.
Innovation Solution
Development of new CD38 Modulating Antibody Agents that specifically bind to CD38, modulating its activity and enhancing immune cell activation and proliferation, while also being compatible with pharmaceutical development and capable of targeting CD38-expressing tumor cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional anti-CD38 antibodies are used to target solid tumors, then CD38-expressing cells can be targeted, but the therapy is ineffective because CD38 expression is generally lower or absent on tumor cells in solid cancers
Solution Approach 1:
The patent applies multi-functionality by designing antibody agents that perform multiple functions simultaneously: they modulate CD38 activity to enhance immune cell activation while also providing targeted cell killing capabilities. This dual functionality allows the therapy to be effective even when CD38 expression on tumor cells is low, as the modulating effect on immune cells compensates for reduced direct tumor targeting.
Solution Approach 2:
The patent uses immune cells as intermediaries to bridge the gap between CD38 modulation and tumor cell killing. By modulating CD38 activity on immune cells (such as T cells and NK cells), the antibody agents enhance immune cell activation and proliferation, which then enables these immune cells to effectively target and kill tumor cells that may have low CD38 expression.
2Strength
If anti-CD38 antibodies are designed to kill CD38-expressing tumor cells directly, then targeted cell killing is achieved, but the therapy fails when CD38 is absent or low on tumor cells
Solution Approach 1:
The antibody agents are designed with multi-functionality, combining CD38 modulating properties with targeted cell killing capabilities. This allows them to maintain effectiveness across different tumor types by adapting their mechanism of action based on CD38 expression levels on both tumor and immune cells.
Solution Approach 2:
The patent inverts the traditional approach by primarily targeting immune cells rather than directly targeting tumor cells. By modulating CD38 activity on immune cells to enhance their activation and killing capabilities, the therapy indirectly achieves tumor cell destruction, reversing the conventional strategy of direct tumor cell targeting.
3Reliability
If CD38 modulating activity is enhanced to improve immune cell activation, then immune response is strengthened, but the complexity of combining multiple activities increases
Solution Approach 1:
The patent employs multi-functionality by designing single antibody agents that simultaneously exhibit CD38 modulating activity and targeted cell killing activity. This approach consolidates multiple therapeutic functions into one agent, enhancing immune cell activation while maintaining manageable complexity through unified molecular design rather than combination therapies.
Solution Approach 2:
The patent merges CD38 modulating properties with targeted cell killing capabilities into a single integrated antibody agent. By combining these activities in one molecule rather than using separate agents, the therapy achieves enhanced immune cell activation and tumor cell killing while reducing the overall complexity of the treatment regimen.
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
The new CD38 Modulating Antibody Agents demonstrate enhanced immune cell activation and cytotoxic properties against CD38-expressing cells, including immune suppressive cells, potentially offering a more effective treatment for solid cancers by modulating CD38 activity and enhancing immune response.
Implementation Method 1
CD38 is a type II membrane receptor glycoprotein having enzymatic activities, in particular as an important ADP-ribosyl cyclase that produces cyclic adenosine diphosphate ribose (cADPR) from nicotinamide adenine dinucleotide.
Implementation Method 2
cADPR is important to the mobilization of intracellular calcium stock that is involved in many cell functions such as cell proliferation, differentiation, adhesion, and signal transduction.
Implementation Method 3
The aCD38-b-348 antibody and variants thereof may exhibit antibody-dependent cell-mediated cytotoxicity (ADCC) activity against CD38+ target cells
Implementation Method 4
Such a positive effect on immune cells may be related to induction of Ca2+ mobilization, inhibition of CD38 enzymatic activity, and/or activation of intra-cellular signaling pathways.
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.