ISB 1342: A FIRST-IN-CLASS CD38 T CELL ENGAGER FOR THE TREATMENT OF RELAPSED REFRACTORY MULTIPLE MYELOMA
Author(s): ,
Mario Perro
Affiliations:
Oncology,Ichnos Sciences,Epalinges,Switzerland
,
Blandine Pouleau
Affiliations:
Oncology,Ichnos Sciences,Epalinges,Switzerland
,
Carole Estoppey
Affiliations:
Oncology,Ichnos Sciences,Epalinges,Switzerland
,
Cian Stutz
Affiliations:
Oncology,Ichnos Sciences,Epalinges,Switzerland
,
Amélie Croset
Affiliations:
Oncology,Ichnos Sciences,Epalinges,Switzerland
,
Amélie Laurendon
Affiliations:
Oncology,Ichnos Sciences,Epalinges,Switzerland
,
Thierry Monnet
Affiliations:
Oncology,Ichnos Sciences,Epalinges,Switzerland
,
Mégane Pluess
Affiliations:
Oncology,Ichnos Sciences,Epalinges,Switzerland
,
Christelle Ries-Fecourt
Affiliations:
Oncology,Ichnos Sciences,Epalinges,Switzerland
,
Julie Macoin
Affiliations:
Oncology,Ichnos Sciences,Epalinges,Switzerland
,
Riccardo Turrini
Affiliations:
Oncology,Ichnos Sciences,Epalinges,Switzerland
,
Perrine Suere
Affiliations:
Oncology,Ichnos Sciences,Epalinges,Switzerland
,
Emilie Nallet
Affiliations:
Oncology,Ichnos Sciences,Epalinges,Switzerland
,
M.Lamine Mbow
Affiliations:
Oncology,Ichnos Sciences,Epalinges,Switzerland
,
Adam Drake
Affiliations:
Oncology,Ichnos Sciences,Epalinges,Switzerland
,
Marie-Agnès Doucey
Affiliations:
Oncology,Ichnos Sciences,Epalinges,Switzerland
Stanislas Blein
Affiliations:
Oncology,Ichnos Sciences,Epalinges,Switzerland
EHA Library. Perro M. 06/09/21; 325696; EP938
Mario Perro
Mario Perro
Contributions
Abstract
Presentation during EHA2021: All e-poster presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: EP938

Type: E-Poster Presentation

Session title: Myeloma and other monoclonal gammopathies - Biology & Translational Research

Background

ISB 1342 is a bispecific antibody heterodimer based on the Ichnos proprietary Bispecific Engagement by Antibodies based on T cell receptor (BEAT®) platform. ISB 1342 is a first-in-class CD38 T cell engager under investigation in subjects with relapsed multiple myeloma refractory to proteasome inhibitors (PIs), immunomodulators (IMiDs) and daratumumab (study ISB 1342-101).

Aims
The aim of this study is to assess on target specificity and potency of ISB 1342 in vitro and in vivo. 

Methods

ISB 1342 was engineered with a single chain variable fragment (scFv) arm that specifically recognizes a cluster of differentiation (CD)3-epsilon (CD3ε) and a fragment antigen binding (Fab) arm which specifically recognizes CD38 and does not compete with daratumumab. By co-engaging CD3ε on T cells and CD38 on tumor cells, ISB 1342 redirects T cells to kill CD38-expressing tumor cells. This mechanism of action is differentiated from existing monospecific CD38 targeting therapies and was designed to overcome resistance to daratumumab in multiple myeloma

Results

In vitro, ISB 1342 killed a large range of CD38-expressing tumor cell lines (EC50:12 to 90 pM) with 8 to 239-fold superior efficacy than daratumumab. ISB 1342 was also able to efficiently kill CD38 low-intermediate-expressing tumor cells that were poorly killed by daratumumab. ISB 1342 retained the potency to kill CD38 low-intermediate-expressing tumor cells when used in sequential or concomitant combination with daratumumab. In addition, the presence of soluble CD38 or glucocorticoid did not impact ISB 1342 killing potency. ISB 1342 was constructed with a double LALA mutation that dampens the binding to Fcγ receptors and C1q. Consistently, ISB 1342 showed only residual Fc-mediated effector functions and its mechanism of tumor cell killing critically relies on the engagement and the activation of T lymphocytes. ISB 1342 showed a favorable on target specificity profile in vitro and was unable to activate T cells in the absence of CD38 positive target cells. Further, ISB 1342-induced tumor cell killing was not associated with a detectable T cell fratricide in vitro. Finally, the potency of ISB 1342 was assessed in vivo in a therapeutic model of a subcutaneously established Daudi tumor co-xenografted with human PBMCs. In marked contrast to daratumumab, which induced only a partial tumor control, ISB 1342 induced complete tumor eradication when injected intravenously weekly at 0.5 mg/kg. As anticipated, the ISB 1342 control molecule (ISB 1342_13DU) made of an irrelevant CD38 binder failed to control tumor growth. The release of the Granzyme A and B, TNF-alpha and CXCL-10 in the tumor micro-environment one week post-treatment was strongly and significantly increased by ISB 1342 but not by daratumumab and ISB 1342_13DU; this represents a correlate of anti-tumor immunity associated with ISB 1342 efficacy in vivo.

Conclusion

Hence the higher potency of ISB 1342 relative to daratumumab supports the ongoing clinical development in multiple myeloma patients.

Keyword(s): Bispecific, Multiple myeloma, T cell activation

Presentation during EHA2021: All e-poster presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: EP938

Type: E-Poster Presentation

Session title: Myeloma and other monoclonal gammopathies - Biology & Translational Research

Background

ISB 1342 is a bispecific antibody heterodimer based on the Ichnos proprietary Bispecific Engagement by Antibodies based on T cell receptor (BEAT®) platform. ISB 1342 is a first-in-class CD38 T cell engager under investigation in subjects with relapsed multiple myeloma refractory to proteasome inhibitors (PIs), immunomodulators (IMiDs) and daratumumab (study ISB 1342-101).

Aims
The aim of this study is to assess on target specificity and potency of ISB 1342 in vitro and in vivo. 

Methods

ISB 1342 was engineered with a single chain variable fragment (scFv) arm that specifically recognizes a cluster of differentiation (CD)3-epsilon (CD3ε) and a fragment antigen binding (Fab) arm which specifically recognizes CD38 and does not compete with daratumumab. By co-engaging CD3ε on T cells and CD38 on tumor cells, ISB 1342 redirects T cells to kill CD38-expressing tumor cells. This mechanism of action is differentiated from existing monospecific CD38 targeting therapies and was designed to overcome resistance to daratumumab in multiple myeloma

Results

In vitro, ISB 1342 killed a large range of CD38-expressing tumor cell lines (EC50:12 to 90 pM) with 8 to 239-fold superior efficacy than daratumumab. ISB 1342 was also able to efficiently kill CD38 low-intermediate-expressing tumor cells that were poorly killed by daratumumab. ISB 1342 retained the potency to kill CD38 low-intermediate-expressing tumor cells when used in sequential or concomitant combination with daratumumab. In addition, the presence of soluble CD38 or glucocorticoid did not impact ISB 1342 killing potency. ISB 1342 was constructed with a double LALA mutation that dampens the binding to Fcγ receptors and C1q. Consistently, ISB 1342 showed only residual Fc-mediated effector functions and its mechanism of tumor cell killing critically relies on the engagement and the activation of T lymphocytes. ISB 1342 showed a favorable on target specificity profile in vitro and was unable to activate T cells in the absence of CD38 positive target cells. Further, ISB 1342-induced tumor cell killing was not associated with a detectable T cell fratricide in vitro. Finally, the potency of ISB 1342 was assessed in vivo in a therapeutic model of a subcutaneously established Daudi tumor co-xenografted with human PBMCs. In marked contrast to daratumumab, which induced only a partial tumor control, ISB 1342 induced complete tumor eradication when injected intravenously weekly at 0.5 mg/kg. As anticipated, the ISB 1342 control molecule (ISB 1342_13DU) made of an irrelevant CD38 binder failed to control tumor growth. The release of the Granzyme A and B, TNF-alpha and CXCL-10 in the tumor micro-environment one week post-treatment was strongly and significantly increased by ISB 1342 but not by daratumumab and ISB 1342_13DU; this represents a correlate of anti-tumor immunity associated with ISB 1342 efficacy in vivo.

Conclusion

Hence the higher potency of ISB 1342 relative to daratumumab supports the ongoing clinical development in multiple myeloma patients.

Keyword(s): Bispecific, Multiple myeloma, T cell activation

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