CD3 BISPECIFIC ANTIBODY SCREEN IDENTIFIES CD20 AS THE MOST EFFICIENT TARGET FOR ELIMINATION OF B CELL MALIGNANCIES; PRE-CLINICAL EVALUATION OF DUOBODY-CD3XCD20
Author(s): ,
Patrick Engelberts
Affiliations:
Genmab,Genmab,Utrecht,Netherlands;Hematology and blood Transfusion,Leiden University Medical Center,Leiden,Netherlands
,
Ida Hiemsta
Affiliations:
Genmab,Genmab,Utrecht,Netherlands
,
Joyce Meesters
Affiliations:
Genmab,Genmab,Utrecht,Netherlands
,
Bart De Jong
Affiliations:
Genmab,Genmab,Utrecht,Netherlands
,
Theodora Salcedo
Affiliations:
Genmab,Genmab,Utrecht,Netherlands
,
Sandra Verploegen
Affiliations:
Genmab,Genmab,Utrecht,Netherlands
,
Edward van den Brink
Affiliations:
Genmab,Genmab,Utrecht,Netherlands
,
Danita Schuurhuis
Affiliations:
Genmab,Genmab,Utrecht,Netherlands
,
Sjeng Horbach
Affiliations:
Genmab,Genmab,Utrecht,Netherlands
,
Aran Labrijn
Affiliations:
Genmab,Genmab,Utrecht,Netherlands
,
Paul Parren
Affiliations:
Hematology and blood Transfusion,Leiden University Medical Center,Leiden,Netherlands
,
Janine Schuurman
Affiliations:
Genmab,Genmab,Utrecht,Netherlands
Esther Breij
Affiliations:
Genmab,Genmab,Utrecht,Netherlands
EHA Learning Center. Engelberts P. Jun 15, 2018; 215079
Patrick Engelberts
Patrick Engelberts
Login now to access Regular content available to all registered users.

Access to EHA Members only content is an EHA membership benefit.
Click here to join EHA or renew your membership here.


Abstract
Discussion Forum (0)
Rate & Comment (0)

Abstract: PF637

Type: Poster Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 17:30 - 19:00

Location: Poster area

Background
The field of immuno-oncology is evolving rapidly through the addition of CD3 bispecific antibody (BsAb) molecules to its arsenal. While such T-cell retargeting bsAb have shown clinical activity in lymphoid malignancies, it is not known which B cell targets are optimally targeted using CD3 BsAb.

Aims

(i) To screen B cell targets suitable for CD3 BsAb targeting, using Genmab’s proprietary bispecific antibody platform, (ii) preclinical development of a highly potent CD3 BsAb to target B cell malignancies in the clinic.

Methods

To identify the most potent B cell-targeting CD3 BsAb, an in vitro functional screen was performed with a panel of CD3 bispecific antibody molecules containing tumor-targeting Fab-arms recognizing the medium-to-highly expressed B-cell surface antigens CD19, CD20, CD22, CD24, CD37, CD70, CD79b, CD138 and HLA-DR. Target binding capacity in vitro was assessed using flow cytometry and the cytotoxic potential towards B cell lymphoma cell lines was tested using chrome-release assays. In vitro T cell activation (determined by the upregulation of CD69, CD25, PD-1) and T cell-mediated cytotoxicity (measured as the reduction in number of remaining tumor cells) of the most potent CD3-BsAb, a CD3xCD20 BsAb designated DuoBody-CD3xCD20, were measured by flow cytometry. Anti-tumor activity in vivo was measured using cell line-derived xenografts in humanized mouse models. Finally, the capacity of DuoBody-CD3xCD20 to induce depletion of normal B cells from peripheral blood and lymphoid structures after intravenous or subcutaneous administration in cynomolgus monkeys was assessed as part of the non-clinical safety studies.

Results

Functional screening of a panel of B cell-targeting CD3 BsAbs in vitro identified multiple targets that could be used to induce T-cell mediated cytotoxicity towards malignant B cells. No correlation between target expression and BsAb-induced T cell-mediated cytotoxicity could be found. CD20-targeting BsAbs were among the most efficient CD3 BsAbs. Specifically, one of the CD3xCD20 BsAbs showed extraordinary potency and outperformed the other CD20-targeting BsAb as well as CD3 BsAbs against all other B cell targets tested. This BsAb, designated DuoBody-CD3xCD20, was shown in vitro to only activate T cells in the presence of B cells and to induce potent T-cell-mediated cytotoxicity of B cell lymphoma cell lines with EC50 values in the low picomolar range. DuoBody-CD3xCD20-dependent T cell-activation and T cell-mediated cytotoxicity resulted in tumor growth inhibition in xenograft models in vivo, both in prophylactic and therapeutic settings. Non-clinical safety studies with DuoBody-CD3xCD20 in cynomolgus monkeys showed potent, long-lasting B cell depletion from both peripheral blood and lymphoid organs. Comparison of intravenous and subcutaneous administration demonstrated lower peak cytokine levels after subcutaneous antibody administration, while bioavailability and the capacity to deplete B cells were comparable to the intravenous route.

Conclusion

DuoBody-CD3xCD20 was identified as the most potent B cell-targeting CD3 BsAb in a panel of BsAbs targeting 9 different B cell targets. In non-clinical safety studies, DuoBody-CD3xCD20 showed efficient depletion of B cells and an acceptable safety profile. The clinical safety of DuoBody-CD3xCD20 (GEN3013) in patients with B cell malignancies will be assessed in a first-in-human study.

Session topic: 19. Non-Hodgkin lymphoma Biology & Translational Research

Keyword(s): antibody, B cell depletion, B cell lymphoma, T cell activation

Code of conduct/disclaimer available in General Terms & Conditions
Anonymous User Privacy Preferences

Strictly Necessary Cookies (Always Active)

MULTILEARNING platforms and tools hereinafter referred as “MLG SOFTWARE” are provided to you as pure educational platforms/services requiring cookies to operate. In the case of the MLG SOFTWARE, cookies are essential for the Platform to function properly for the provision of education. If these cookies are disabled, a large subset of the functionality provided by the Platform will either be unavailable or cease to work as expected. The MLG SOFTWARE do not capture non-essential activities such as menu items and listings you click on or pages viewed.


Performance Cookies

Performance cookies are used to analyse how visitors use a website in order to provide a better user experience.



Google Analytics is used for user behavior tracking/reporting. Google Analytics works in parallel and independently from MLG’s features. Google Analytics relies on cookies and these cookies can be used by Google to track users across different platforms/services.


Save Settings