-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

1408 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

Program: Oral and Poster Abstracts
Session: 605. Molecular Pharmacology and Drug Resistance: Lymphoid Neoplasms: Poster I
Hematology Disease Topics & Pathways:
Research, Translational Research
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Lorena Fontan, PhD1, Adam Zwolak2*, Irene Guimerans-Lorenzo1*, Mariette Bekkers1*, Nicholas Hein2*, Nele Vloemans1*, Emanuele Trella1*, Tina Smets1*, Ivo Cornelissen1*, Alemu Assefa1*, Bie Verbist, PhD1*, Ricardo Amorim, PhD1*, Pankaj Seth, PhD2*, Ranjeet Prasad Dash2*, Leopoldo Luistro, PhD2*, Bethany Mattson, PhD2*, Matthew A. Dragovich3*, Michael Hedvat3*, Gregory L. Moore3*, John R. Desjarlais, PhD3*, Olivia Kutlu4*, Joseph Erhardt2* and Ulrike Philippar, PhD1

1Janssen Research & Development, Beerse, Belgium
2Janssen Research & Development, Spring House, PA
3Xencor, Inc., Pasadena, CA
4Janssen Research & Development, Los Angeles, CA

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<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<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.

Disclosures: Fontan: Janssen Research & Development: Current Employment, Current holder of stock options in a privately-held company. Zwolak: Janssen Research & Development: Current Employment, Current holder of stock options in a privately-held company. Guimerans-Lorenzo: Janssen Research & Development: Current Employment, Current holder of stock options in a privately-held company. Bekkers: Janssen Research & Development: Current Employment, Current holder of stock options in a privately-held company. Hein: Johnson and Johnson Innovative Medicine: Current Employment, Current equity holder in publicly-traded company. Vloemans: Janssen Research & Development: Current Employment, Current holder of stock options in a privately-held company. Trella: Janssen Research & Development: Current Employment, Current holder of stock options in a privately-held company. Smets: Janssen Research & Development: Current Employment, Current holder of stock options in a privately-held company. Cornelissen: Janssen Research & Development: Current Employment, Current holder of stock options in a privately-held company. Assefa: Janssen Research & Development: Current Employment, Current holder of stock options in a privately-held company. Verbist: Janssen Research & Development: Current Employment, Current holder of stock options in a privately-held company. Amorim: Janssen Research & Development: Current Employment, Current holder of stock options in a privately-held company. Seth: Janssen Research & Development: Ended employment in the past 24 months. Dash: Janssen Research & Development: Current Employment, Current holder of stock options in a privately-held company. Luistro: Janssen Research & Development: Current Employment, Current holder of stock options in a privately-held company. Mattson: Janssen Research & Development: Current Employment, Current holder of stock options in a privately-held company. Dragovich: Xencor, Inc.: Current Employment. Hedvat: Xencor, Inc.: Current Employment. Moore: Xencor, Inc.: Current Employment. Desjarlais: Xencor, Inc.: Current Employment. Kutlu: Janssen Research & Development: Current Employment, Other: Current holder of stock options in a public company. Erhardt: Janssen Research & Development: Ended employment in the past 24 months. Philippar: Johnson&Johnson Innovative Medicine: Current Employment, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

*signifies non-member of ASH