- Posters presented at the 63rd American Society of Hematology Annual Meeting -
“Our novel anti-CD47 antibody and CD20xCD3 bispecific TCE programs successfully leverage SAFEbody technology for precision masking to decouple efficacy from the toxicities that are often associated with therapeutic modalities for these two important targets on the forefront of clinical development for hematologic malignancies,” said
ADG153 (Anti-CD47 SAFEbody)
Key findings from the poster (#3342) titled “ADG153, an Anti-CD-47 Monoclonal Antibody Prodrug, Has Strong In
- Given the dose-limiting hematologic toxicity and antigen sink liability associated with current anti-CD47 antibodies in clinical development,
Adagenehas developed an anti-CD47 SAFEbody with precision masking for preferential binding on CD47 overexpressed on tumor versus normal cells. To realize the full potential of anti-CD47 therapy for both hematologic and solid malignancies, the SAFEbody technology enables IgG1-mediated strong effector functions for potent tumor killing, while minimizing antigen sink and red blood cell (RBC) depletion with an approximately 8-fold prolonged half-life for convenient drug dosing and administration.
- An anti-CD47 ADG153-G4 SAFEbody was designed for benchmarking and evaluated in preclinical studies in comparison with its parental antibody, and analogs of magrolimab (Hu5F9) and lemzoparlimab (TJC4) in IgG4 format with the following findings:
- ADG153-G4 parental antibody and its activated SAFEbody can block the CD47 signal by targeting a unique epitope of CD47 with high affinity and minimal RBC hemagglutination.
- In preclinical studies in monkeys, ADG153-G4 showed a significantly less decrease in RBCs and hemoglobin at the 10, 30 and 60 mg/kg dose levels compared to Hu5F9 at 10 mg/kg, addressing the hematologic toxicities inherent in current anti-CD47 therapies in development.
- ADG153-G4 SAFEbody also showed its 8-fold prolonged half-life by overcoming the antigen sink observed with other anti-CD47 therapies in development.
- Only antibody-dependent cellular phagocytosis (ADCP) effector function was detected for anti-CD47 antibodies in IgG4 isotype via CD47-mediated phagocytosis by macrophage.
- An anti-CD47 ADG153-G1 SAFEbody was designed to maximize tumor killing via IgG1-mediated effector functions unlike many other anti-CD47 therapies in development:
- ADG153-G1 induced potent antibody-dependent cellular cytotoxicity (ADCC); as expected, none was observed for the IgG4 benchmark antibodies.
- ADG153-G1 induced stronger ADCP activity than the IgG4 benchmark antibodies.
- Preclinical results concluded that the ADG153-G1 can achieve potent anti-CD47 efficacy with a well-tolerated safety profile, providing a strong rationale to advance this candidate into clinic. Currently, no other known anti-CD47 antibodies using the IgG1 isotype are in clinical development.
- Notably, ADG153-G1 was well tolerated at 10 mg/kg, with only an 8 percent decrease in RBCs, compared to a 49 percent decrease with Hu5F9 in IgG4 format. For reference, it has been reported in the literature that another IgG1 anti-CD47 antibody can cause more than a 40 percent decrease in RBCs at 1 mg/kg.
- After a single intravenous dose, ADG153-G1 demonstrated an approximately 8-fold longer apparent half-life and 5-fold higher area under the curve (AUC) at 10mg/kg than Hu5F9.
- Taken together, these preclinical findings suggest that the ADG153-G1 SAFEbody integrates safety (by precision masking) and efficacy (by IgG1-mediated ADCC and ADCP) into one single modality for a best-in-class product profile, presenting the exciting opportunity to maximize potential of anti-CD47 therapy - ultimately aimed for solid malignancies.
ADG152 (CD20xCD3 POWERbody)
Key findings from the poster (#1204) titled “ADG152, a Novel CD20xCD3 T-Cell Engager Prodrug with Enhanced Therapeutic Index, Demonstrates Strong Anti-Tumor Activity with Improved Safety” include:
- ADG152 is a bispecific CD20xCD3 T-cell engager POWERbody that integrates SAFEbody precision masking technology to minimize cytokine release syndrome (CRS) and on-target/off-tumor toxicities for an increased therapeutic index.
- The anti-CD20 arm of ADG152 has enhanced the binding to CD20, while its anti-CD3 arm has tailor made affinity for CD3 using SAFEbody technology.
- At a 100-fold higher dose, ADG152 at 30 mg/kg resulted in significantly less cytokine induction (as measured by IFN-γ and IL-2 levels) than an analog of plamotamab at 0.3 mg/kg.
- In preclinical models, ADG152 resulted in dose-dependent anti-tumor activity with almost complete tumor growth inhibition when dosed at 1.5 mg/kg.
- ADG152 induced strong and sustained B-cell depletion across different dose levels.
- ADG152 also demonstrated improved pharmacokinetics in monkeys versus the plamotamab analog, with approximately a 2-fold longer half-life (7-13 days at 0.3 - 30mg/kg) and approximately an 8-fold higher AUC after a single intravenous injection.
“CRS has been a longstanding challenge of T-cell engagers and has limited the ability to safely provide high levels of activity during initial dosing,” said
Both ADG153 and ADG152 are potential Investigational New Drug candidates from Adagene’s growing portfolio of preclinical discovery programs, five of which are in IND-enabling studies. The preclinical data presented at ASH provide a strong rationale for advancing these potentially best-in-class candidates into clinical development.
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This press release contains forward-looking statements, including statements regarding the potential implications of preclinical results, and Adagene’s advancement of, and anticipated clinical activities, clinical development and regulatory milestones of its product candidates. Actual results may differ materially from those indicated in the forward-looking statements as a result of various important factors, including but not limited to Adagene’s ability to demonstrate the safety and efficacy of its drug candidates; the clinical results for its drug candidates, which may not support further development or regulatory approval; the content and timing of decisions made by the relevant regulatory authorities regarding regulatory approval of Adagene’s drug candidates; Adagene’s ability to achieve commercial success for its drug candidates, if approved; Adagene’s ability to obtain and maintain protection of intellectual property for its technology and drugs; Adagene’s reliance on third parties to conduct drug development, manufacturing and other services; Adagene’s limited operating history and Adagene’s ability to obtain additional funding for operations and to complete the development and commercialization of its drug candidates; Adagene’s ability to enter into additional collaboration agreements beyond its existing strategic partnerships or collaborations, and the impact of the COVID-19 pandemic on Adagene’s clinical development, commercial and other operations, as well as those risks more fully discussed in the “Risk Factors” section in Adagene’s filings with the
Source: Adagene, Inc.