PBD Antibody Drug Conjugate Combinations with BCL-2 Inhibitors
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current antibody drug conjugates (ADCs) have limitations in effectively treating all patients, particularly those with high Bcl-2 expression or function in cancers like acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL), as not all patients respond to single-agent ADCs.
Innovation Solution
Combining an antibody drug conjugate (ADC) specifically binding to CD33, CD123, or CD19 proteins with the Bcl-2 inhibitor ABT-199 (venetoclax) to enhance treatment efficacy in cancers with high Bcl-2 expression, where the ADC comprises specific antibody variable regions and a PBD cytotoxic agent.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a single-agent ADC is used to treat cancer, then the treatment is simpler and has fewer side effects, but not all patients respond and treatment efficacy is insufficient for cancers with high Bcl-2 expression
Solution Approach 1:
The patent combines an ADC (such as anti-CD33, anti-CD123, or anti-CD19 ADC conjugated to PBD cytotoxic agents) with a Bcl-2 inhibitor (ABT-199/venetoclax) into a dual-agent treatment regimen. This merging of two different therapeutic mechanisms addresses the limitation of single-agent ADC therapy by simultaneously targeting cancer cells through antibody-mediated cytotoxicity and overcoming Bcl-2-mediated drug resistance, thereby improving overall treatment efficacy for patients who do not respond to ADC alone.
2Reliability
If combination therapy with ADC and Bcl-2 inhibitor is used, then treatment efficacy is improved for patients with high Bcl-2 expression, but the treatment becomes more complex and may increase side effects
Solution Approach 1:
The ADC component provides targeted delivery of the PBD cytotoxic agent specifically to cancer cells expressing the relevant antigen (CD33, CD123, or CD19), concentrating the therapeutic effect locally at the tumor site while minimizing exposure to healthy tissues. This targeted approach allows the use of potent cytotoxic agents and combination therapy while reducing systemic side effects, as the ADC acts as a delivery vehicle that spares non-targeted cells.
Data Source
Figure 1
Figure 2
Figure 3
AI summary
This invention relates to treatment of cancer using antibody drug conjugates that comprise PBD molecules in combination with Bcl-2 inhibitors.