Anti-CD38/CD28xCD3 Trispecific T cell Engager for the Treatment of Multiple Myeloma

With Nizar El-Murr, Principal Scientist and Lab Head, Immuno-Oncology Research at Sanofi Summary by Candace Kastanis

Anti-CD38/CD28xCD3 Trispecific T cell Engager for the Treatment of Multiple Myeloma

Candace Kastanis looks back on a talk focused on Multiple Myeloma delivered by Nizar El-Murr, Principal Scientist and Lab Head - Immuno-Oncology Research at Sanofi

El-Murr began his presentation with providing interesting background information on Multiple Myeloma, a cancer of the plasma cells. He indicated it is considered a rare cancer type and represented about 1% of all cancers in 2020.Treatment modalities have improved significantly over the years, with the most recent being cell-based therapies. The treatment landscape including cellular therapies show immense potential to improved patient outcomes although multiple myeloma is still considered a non-curable disease.CD38 (Antibodies Daratumumab and Isatuximab based Therapy) as a Breakthrough TreatmentThe mechanism of action of anti-CD38 relies upon recruiting the immune system by their Fc portion and kills the tumour cells directly proving its effectiveness in treating MM.

However, the research aim was to create a 2nd generation of CD38 that would serve as an additional compliment to other therapies and hopefully eliminating resistance and potential relapses. Additionally, it is a t-cell engager that offers:

High and prolonged efficacy against MM T-cell engagement

Robust activity on CD38 high and low expressing cells

Acceptable safety profile, mostly in terms of cytokine release characteristic to these types of compounds

The enhanced mechanism of action of the new anti-38 arm features:

Recruitment of T-cells to tumour cells via anti-CD38

Activation of engaged T-cells via anti CD3/CD28

Lysing of tumour cells through Perforin/Granzyme mechanism

Exploring the use of a Trispecific Platform as a Therapeutic Option for MMEl-Murr introduced the Crossover Dual Variable Format or CODV format. He explains why the trispecific platform was chosen and illustrated how the platform allows the integration of both the anti CD3 and CD28.This platform was engineered to be used with any circulating membrane bound targets. A reference to prior journal paper was introduced giving detailed information about the use of a trispecific platform.

Benefits of CD28 Arm:

Induces survival and proliferation of primary T cells

Negative regulators activation cell death. Helps retain immune tolerance

Bcl -xl negative regulator

Enhances the expression bcl

Site specific knockouts

Proliferation of primary MM bone marrow T cells

Important Characteristics of CD38/CD28xCD3:

In vitro activity of the Cd38/CD28xCD3 TCE is active on both CD 38 high and low expressing cells which are necessary for optimal activity

Ex vivo T-cell mediated lysis of CD38 + RPMI-8226

CD28 increases expression on MM cells and increases susceptibility to cytolysis. CD38/CD28xCD3 TCE lacking the anti-CD28 and CD38 vs CD38 alone

When CD28 mediates binding of binding CD38/CD28xCD3 TCE to cells when CD38 is occupied/inaccessible

ConclusionCD38/CD28xCD3 antibody is a trispecific T-cell engager designed for the treatment of multiple myeloma.The mechanism of action is dependent on the expression of CD38 by malignant plasma cells and the recruitment and activation of T-cells via CD3 (signal 1 and CD28 signal 2).CD28 induces survival and proliferation of primary T cells and in a monovalent format does induce elevated levels of cytokines. CD38/CD28xCD3 is active on both CD38 high and CD38 low MM cells and has shown superiority in some in-vitro assays vs. other CD38 based therapies (e.g., daratumumab). CD38/CD28xCD3 TCE can also induce the proliferation and activate MM patient-derived bone marrow T cells.MM cells also express CD28 on their membrane. CD28 expressed on MM tumor cells can be directly targeted by CD38/CD28xCD3 TCE.Additionally, it acts as a good second target antigen contributing to more effective when low CD38 expressions arise naturally or is selected by previous anti CD38 antibody therapy.