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Preclinical Development of SGN-CD47M: Protease-Activated Antibody Technology Enables Selective Tumor Targeting of the
Matthew R Levengood1, Christopher M Carosino1, Xinqun Zhang1
1Pfizer, Inc., Bothell, Washington.
Abstract:
CD47 is a cell-surface glycoprotein that is expressed on normal human tissues and plays a key role as a marker of self. Tumor cells have co-opted CD47 overexpression to evade immune surveillance, and thus blockade of CD47 is a highly active area of clinical exploration in oncology. However, clinical development of CD47-targeted agents has been complicated by its robust expression in normal tissues and the toxicities that arise from blocking this inhibitory signal. Furthermore, pro-phagocytic signals are not uniformly expressed in tumors, and antibody blockade alone is often not sufficient to drive antitumor activity. The inclusion of an IgG1 antibody backbone into therapeutic design has been shown to not only serve as an additional pro-phagocytic signal but also exacerbate toxicities in normal tissues. Therefore, a need persists for more selective therapeutic modalities targeting CD47. To address these challenges, we developed SGN-CD47M, a humanized anti-CD47 IgG1 mAb linked to novel masking peptides through linkers designed to be cleaved by active proteases enriched in the tumor microenvironment (TME). Masking technology has the potential to increase the amount of drug that reaches the TME while concomitantly reducing systemic toxicities. We demonstrate that SGN-CD47M is well tolerated in cynomolgus monkeys and displays a 20-fold improvement in tolerability to hematologic toxicities when compared with the unmasked antibody. SGN-CD47M also displays preferential activation in the TME that leads to robust single-agent antitumor activity. For these reasons, SGN-CD47M may have enhanced antitumor activity and improved tolerability relative to existing therapies that target the CD47-signal regulatory protein α interaction.
Insights
A novel CD47-blocking antibody, SGN-CD47M, uses masking technology to improve tolerability and enhance antitumor activity. This approach reduces toxicities in normal tissues while increasing drug concentration in the tumor microenvironment.
Area of Science:
- Oncology
- Immunotherapy
- Biotechnology
Background:
- CD47 is a self-marker overexpressed by tumors to evade immune surveillance.
- CD47 blockade is a promising cancer therapy, but normal tissue expression causes toxicity.
- Current therapies face challenges with efficacy and side effects due to CD47's broad expression.
Purpose of the Study:
- To develop a more selective and tolerable CD47-targeted therapeutic.
- To investigate the efficacy and safety of a novel masked antibody, SGN-CD47M.
- To assess the potential of masking technology in improving CD47-targeted cancer treatment.
Main Methods:
- Development of SGN-CD47M, an anti-CD47 antibody with tumor-microenvironment-cleavable masking peptides.
- Preclinical evaluation in cynomolgus monkeys to assess tolerability and hematologic toxicity.
- Assessment of SGN-CD47M's preferential activation in the tumor microenvironment and its single-agent antitumor activity.
Main Results:
- SGN-CD47M demonstrated a 20-fold improvement in tolerability to hematologic toxicities compared to the unmasked antibody.
- The masked antibody showed preferential activation within the tumor microenvironment.
- SGN-CD47M exhibited robust single-agent antitumor activity.
Conclusions:
- SGN-CD47M offers enhanced tolerability by reducing systemic toxicities associated with CD47 blockade.
- The masking technology allows for targeted drug delivery to the tumor microenvironment.
- SGN-CD47M represents a promising therapeutic candidate with potential for improved antitumor efficacy and safety over existing CD47-targeting agents.
