Anti-CD47 Dosing Regimens for Hematologic Malignancies
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Hematologic malignancies, such as leukemias, pose a challenge in achieving effective therapy due to the risk of toxicity from high circulating tumor cell burdens, which can occur if anti-CD47 agents are escalated too quickly.
Innovation Solution
The methods involve determining and administering optimized dosing regimens for anti-CD47 agents, including initial sub-therapeutic doses or cytoreductive therapies to reduce circulating tumor cells, followed by dose escalation to achieve therapeutic levels with greater than 80% receptor occupancy in bone marrow blast cells, and maintenance of this level to reduce tumor cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If the dose of anti-CD47 agent is escalated quickly to achieve therapeutic benefit, then the therapeutic effect is improved, but the toxicity from high circulating tumor cell lysis increases
Solution Approach 1:
The patent applies preliminary action by administering a cytoreductive agent before the anti-CD47 agent to reduce the circulating tumor cell burden. This preparatory step ensures that when the anti-CD47 agent is subsequently administered at therapeutic doses, the toxic effects from rapid tumor cell lysis are minimized while still achieving effective therapeutic benefit.
2Reliability
If the dose of anti-CD47 agent is escalated slowly to prevent toxicity, then the safety is improved, but the time to achieve therapeutic benefit increases
Solution Approach 1:
By performing cytoreduction as a preliminary action before anti-CD47 therapy, the patent enables faster dose escalation of the anti-CD47 agent without safety concerns. The preliminary reduction of circulating tumor cells creates a safe window that allows rapid achievement of therapeutic doses, thus reducing the overall treatment time while maintaining safety.
Solution Approach 2:
The treatment is segmented into distinct phases: a preliminary cytoreductive phase followed by an anti-CD47 therapy phase. This segmentation allows each phase to be optimized independently - the cytoreductive phase manages safety by reducing tumor burden, while the anti-CD47 phase maximizes therapeutic effect through rapid dose escalation, thereby resolving the time-safety contradiction.
3Productivity
If a high dose of anti-CD47 agent is administered to clear bone marrow tumor cells, then the therapeutic efficacy is improved, but the risk of early mortality from tumor lysis syndrome increases
Solution Approach 1:
The patent applies preliminary cytoreductive therapy to reduce the overall tumor burden before administering high doses of anti-CD47 agent. This preliminary action decreases the pool of tumor cells available to cause toxic lysis, thereby enabling safe administration of high therapeutic doses that effectively clear bone marrow tumor cells without excessive risk of tumor lysis syndrome.
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
This approach allows for safe escalation of anti-CD47 agent doses, preventing early mortality and enabling effective clearance of leukemic cells while minimizing toxicity.
Implementation Method 1
SIRPα inhibits the phagocytosis of host cells by macrophages, where the ligation of SIRPα on macrophages by CD47 expressed on the host target cell generates an inhibitory signal mediated by SHP-1 that negatively regulates phagocytosis.
Data Source
AI summary
Methods are provided herein for determining and administering optimized dosing of therapeutic anti-D47 agents, in a schedule that provides safe escalation of dose while achieving a therapeutic level in a clinically effective period of time. The methods can comprise the steps of clearance, escalation, and maintenance. In one embodiment the dosing regimen administers an initial (i) sub-therapeutic dose of an anti-CD47 agent or (ii) a cytoreductive therapy to achieve a safe level of circulating tumor cells for subsequent treatment (clearance); escalating the dose of an anti-CD47 agent until a therapeutic dose is reached (escalation); and maintaining the therapeutic dose for a period of time sufficient to reduce tumor cells in the bone marrow of the patient (maintenance). In an alternative dosing regimen, a patient determined to have a safe level of circulating tumor cells at presentation is treated by the steps of escalation and maintenance without initial clearance.