Related Experiment Video
Updated: Sep 20, 2025
Analyzing Tumor and Tissue Distribution of Target Antigen Specific Therapeutic Antibody
Published on: May 16, 2020
A Novel Affinity Engineered Anti-CD47 Antibody With Improved Therapeutic Index That Preserves Erythrocytes and Normal
Youg R Thaker1, Ianne Rivera1,2, Christophe Pedros1,3
1Sorrento Therapeutics, Inc., San Diego, CA, United States.
Abstract:
Therapeutic blockade of the CD47/SIRPα axis by small molecules or monoclonal antibodies (mAbs) is a proven strategy to enhance macrophages-mediated anti-tumor activity. However, this strategy has been hampered by elevated on-target toxicities and rapid clearance due to the extensive CD47 expression on normal cells ("antigen sink") such as red blood cells (RBCs). To address these hurdles, we report on the development of STI-6643, an affinity-engineered fully human anti-CD47 IgG4 antibody with negligible binding to normal cells. STI-6643 exhibited no hemagglutination activity on human RBCs at concentrations up to 300 µg/mL yet specifically blocked the CD47/SIPRα interaction. Of particular interest, STI-6643 preserved T cell functionality in vitro and showed significantly lower immune cell depletion in vivo in contrast to three previously published competitor reference anti-CD47 clones Hu5F9, AO-176 and 13H3. In cynomolgus monkeys, STI-6643 was well-tolerated at the highest dose tested (300 mg/kg/week) and provided favorable clinical safety margins. Finally, STI-6643 displayed comparable anti-tumor activity to the high-affinity reference clone Hu5F9 in a RAJI-Fluc xenograft tumor model as monotherapy or in combination with anti-CD20 (rituximab) or anti-CD38 (daratumumab) mAbs. These data suggest that STI-6643 possesses the characteristics of an effective therapeutic candidate given its potent anti-tumor activity and low toxicity profile.
Insights
A new anti-CD47 antibody, STI-6643, effectively targets cancer cells while minimizing toxicity to normal cells like red blood cells. This engineered antibody shows promise as a safer therapeutic option for enhancing anti-tumor immunity.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Therapeutic blockade of the CD47/SIRPα axis enhances macrophage-mediated anti-tumor activity.
- High expression of CD47 on normal cells causes on-target toxicities and rapid clearance of anti-CD47 therapies.
- Existing anti-CD47 antibodies face challenges due to significant side effects on healthy tissues.
Purpose of the Study:
- To develop an affinity-engineered anti-CD47 antibody, STI-6643, with reduced binding to normal cells.
- To evaluate the safety and efficacy profile of STI-6643 compared to existing anti-CD47 antibodies.
- To assess the therapeutic potential of STI-6643 as a monotherapy and in combination regimens.
Main Methods:
- Development of a fully human IgG4 anti-CD47 antibody (STI-6643) with engineered affinity.
- Assessment of hemagglutination activity and CD47/SIRPα blocking in vitro.
- Evaluation of T cell functionality and in vivo immune cell depletion.
- Pharmacokinetic and safety studies in cynomolgus monkeys.
- In vivo efficacy studies in a RAJI-Fluc xenograft model.
Main Results:
- STI-6643 demonstrated no hemagglutination of human red blood cells up to 300 µg/mL.
- STI-6643 specifically blocked the CD47/SIRPα interaction, preserved T cell function, and showed lower in vivo immune cell depletion than competitors.
- STI-6643 was well-tolerated in cynomolgus monkeys with favorable safety margins.
- Comparable anti-tumor activity to Hu5F9 was observed in xenograft models, both as monotherapy and in combination therapies.
Conclusions:
- STI-6643 is a promising therapeutic candidate with potent anti-tumor activity and a significantly improved safety profile.
- Its ability to selectively target cancer cells while sparing normal tissues addresses key limitations of previous anti-CD47 therapies.
- STI-6643 offers a potential advancement in cancer immunotherapy, particularly for hematological malignancies.
More Related Videos
08:46A Real-time Potency Assay for Chimeric Antigen Receptor T Cells Targeting Solid and Hematological Cancer Cells
Published on: November 12, 2019
07:52Detection of Antibodies That Neutralize the Cellular Uptake of Enzyme Replacement Therapies with a Cell-based Assay
Published on: September 10, 2018