JNJ-87801493 (CD20xCD28), a Potential First-in-Class CD20 Targeted CD28 Costimulatory Bispecific Antibody, Enhances the Activity of B-Cell Targeting T-Cell Engagers in Preclinical Models
Authors: Fontan Lorena , Zwolak Adam , Guimerans-Lorenzo Irene , Bekkers Mariette , Hein Nicholas , Vloemans Nele , Trella Emanuele , Smets Tina , Cornelissen Ivo , Assefa Alemu , Verbist Bie , Amorim Ricardo , Seth Pankaj , Dash Ranjeet Prasad , Luistro Leopoldo , Mattson Bethany , Dragovich Matthew A. , Hedvat Michael , Moore Gregory L. , Desjarlais John R. , Kutlu Olivia , Erhardt Joseph , Philippar Ulrike 
Published: December 2024

Optimal T-cell activation arises from engagement of the T-cell receptor ('Signal 1') along with positive costimulatory signaling ('Signal 2'). CD28 is a positive costimulatory signaling molecule expressed constitutively by T-cells that binds to CD80 and CD86 on antigen-presenting cells; CD28 receptor engagement initiates 'Signal 2' pathways important for T-cell activation, differentiation, persistence, and survival.

T-cell engagers (TCE) are multispecific antibodies that engage a target antigen on tumor cells and CD3 on T-cells providing a 'Signal 1' and relying on the activity of endogenous T-cells to clear the tumor. However, the immunosuppressive tumor micro-environment can restrict the costimulatory signaling provided to T-cells, potentially limiting the anti-tumor activity of TCEs. Mimicking the natural 'Signal 2' with a bispecific costimulatory antibody targeting CD28 and a tumor associated antigen, administered together with a TCE, may enable optimal activation and persistence of T-cells. This combination pharmacology approach could trigger both 'Signal 1' and 'Signal 2' simultaneously, potentially leading to enhanced tumor lysis and increased response rate, depth, and durability of TCE therapies.

JNJ-87801493 (CD20xCD28) is a novel, fully human, IgG1 bispecific costimulatory antibody that binds to CD20 on B-cells and the CD28 receptor on T-cells. JNJ-87801493 features a disulfide-stapled single-chain fragment variable (scFv) that binds to CD28 monovalently with relatively weak affinity and without superagonism.

In in vitro combination studies with JNJ-80948543 (CD79b x CD20 x CD3 TCE), JNJ-87801493 synergistically enhanced T-cell dependent cytotoxicity against several B-cell non-Hodgkin lymphoma (B-NHL) cell lines using isolated T-cells from healthy donors. In addition, JNJ-87801493 enhanced JNJ-80948543-mediated T-cell activation in a concentration-dependent manner in several B-NHL cell lines using isolated T-cells from healthy donors. JNJ-87801493 had no effect on T-cell activation or T-cell mediated cytotoxicity in a negative cell line which does not express CD20 or CD79b, in the presence or absence of TCE.

In an established subcutaneous B-NHL xenograft model (OCI-Ly10), JNJ-87801493 alone at 0.5 mg/kg did not affect OCI-Ly10 tumor growth compared to Dulbecco's Phosphate-Buffered Saline (DPBS) control treatment, while treatment with JNJ-80948543 at a low but pharmacologically active concentration of 1 mg/kg resulted in 44% tumor growth inhibition (p=0.0191) as compared to DPBS control treatment on Day 31. Combination treatment with JNJ-80948543 (1 mg/kg) and JNJ-87801493 (0.5 mg/kg) exhibited statistically significant antitumor efficacy (75% tumor growth inhibition, p&lt;0.001) compared to DPBS treatment on Day 31. By Day 38, combination treatment with JNJ-80948543 (1 mg/kg) and JNJ-87801493 (0.5 mg/kg) exhibited statistically significant antitumor efficacy compared to JNJ-80948543 monotherapy at 1 mg/kg (p&lt;0.001) and resulted in 97% tumor regression with 2 of 8 partial responses and in 6 of 8 complete responses by Day 62.

In conclusion, our data establishes the preclinical activity of JNJ-87801493 and its impact on the in vitro and in vivo efficacy of TCEs through improved T-cell function. A clinical trial (NCT06139406) is underway to characterize the safety and clinical activity of JNJ-87801493 in combination with JNJ-80948543 in participants with previously treated B-cell NHL.