T-Cell redirecting Antibodies for the Treatment of Hematological Malignancies

Philippar, PhD, Senior Director Oncology, Global Head of Discovery Hematological Malignancies at Janssen R&D

Ulrike Phillippar, PhD, the Senior Director of Oncology, and Global Head of Discovery Hematological Malignancies at Janssen R&D, highlighted the areas of focus that Janssens Therapeutics aims to address via novel drug candidates and other scientifically engineered platforms and product offerings. The clinical data presented in the presentation discussed several notable projects included in their developmental pipeline: Darzalez (- ADCC, CDC manufactured-type antibodies), CD3 Redirected Therapies (Teclistamab [BCMAxCD3], Talquetamab [GPRC5DxCD3]), and cell therapy (CILTA-cell [BCMA-CART]). The mission of Janssens Therapeutics states a goal of eliminating blood cancers by delivering the next generation of viral therapeutics.

About BCMA: B-Cell Maturation Antigen

Phillippar explained that BCMA is a Type 3 transmembrane protein – tumor necrosis factor superfamily 17 (TNTRSF17). The BCMA expression is restricted to B-cell lineage and highly expressed in Multiple Myeloma (MM) plasma cells. Involved in B-cell lineage and highly expressed in MM plasma cells (PCs), April and BAFF are ligands involved in MM growth and proliferation. BCMA knock-out mice demonstrates viability, and normal-B and T-cells, show lack of long-lived plasma cells (PCs).

About GPRC5D: Protein-Coupled Receptor Class C Group 5 Member D

Phillippar also provided a description of GPRC5D, which is an orphan G protein-coupled receptor of unknown function that demonstrates little expression in healthy human tissue in plasma cells and hair follicles. The research found it to have high expression in myeloma cells and an association with poor prognostic factors relative to MM. There are no known shed peptides or extracellular domain shedding (reduced risk for sink effect) associated with GPRC5D. The research concludes that GPR5D possesses attributes of an ideal target for CD3 redirection and, subsequently, a viable therapeutic candidate.

Pre-Clinical Data for BCMA and GPRC5D.

BCMA, and GPRC5D may be expressed together, and data was obtained by collecting 51 patient samples. The analyzed patient data demonstrated expression of one or both markers in the samples. The findings led to advanced engineering for the generation of bispecific T-cell redirection antibodies targeting BCMA or GPRC5D.

Generation of Bispecific T-cell Redirection Antibodies Targeting BCMA or GPRC5D

Multiple Immunizations (omni-rats, phage, mice)

IG4PAA (reduced Fc Binding)

Duobody Technology ™(GenMab)

Functional Assessment (en vivo, ex vivo, en vitro)

BCMA + CD3 = Teclistamab (BCMAxCD3)

GPRC5D + CD3 = Talquetamab (GPRC5DxCD3)

Understanding How T-Cell Redirection Works in MM Patients

Phillippar shared that the research method used describes a strategy for making the affinity for the cancer cell higher than the T-cell, so that the antibody first aligns with the targeted cancer cell and then recruits the T-cell, the (CD3 arm). This activity allows the synapse between the T-cell and the myeloma cell to be formed. Activation of the T-cell then results in release of cell-death precursory enzymes leading to an apoptosis cascade within the myeloma cell.

Efficacy Models and Antibody Characterization

Both antibody candidates, Teclistamab (BCMAxCD3) and Talquetamab (GPRC5DxCD3) demonstrate the capacity to elicit target specific cytotoxicity and T-cell activation in multiple MM models.Both antibody candidates, Teclistamab (BCMAxCD3) and Talquetamab (GPRC5DxCD3) induce cytotoxicity of MM primary patient samples.Teclistamab (BCMAxCD3), specifically, did not show any agnostic activity and is not affected by soluble BCMA in vitro.Talquetamab (GPRC5DxCD3) is shown to mediate MM cell lysis when mixed with whole blood (healthy cells) and exhibited anti-tumor activity in MM xenograft cell models.

Clinical Findings and Endpoints for Teclistamab

MajesTEC1 Response Rate to Teclistamab

Overall Response Rate of 63% representing a substantial benefit for patients with triple class exposed disease.

Response rate remained high at 63 % with a complete response rate or better achieved in 39.4% of the patients.

Median Duration of Response of 18.4 months (about 1one and a half years) and in those achieving a CR or better, event-free rate was 80.1% at 12 months. Median PFS of 11. 3 months.

After median-follow up of 14 months, teclistamab yields deep and durable responses in patients with highly refractory MM.

Toxicities were manageable.

CRS was predominantly grade ½ and incidence of neuro-toxic events were low.

Cytopenia and infections were common but consistent with heavily pretreated RRMM.

Conclusion

Bispecific antibodies can efficiently recruit T cells and lead cytotoxicity in a target-specific manner. Both antibody candidates, Teclistamab (BCMAxCD3) and Talquetamab (GPRC5DxCD3) demonstrate antitumor efficacy that correlates with T-cell infiltration. The clinical data and related findings indicate both drug candidates as promising new off-the-shelf T-cell redirecting therapy targeting BCMA for patients with RRMM. Phase 3 clinal trials are underway, in addition to pre-approval access programs.Future research projects may focus to gaining a deeper understanding of resistance mechanisms and recruitment of different immune cell populations. Other directional areas include targeting other surface proteins, identifying adjacent affinity solutions with different CD3 binders, and combinations (e.g., co-stimulation)