This presentation will describe key preclinical data from Regeneron’s new clinical approaches to enhancing anti-tumor efficacy, focusing on the combination of costimulatory bispecific antibodies with checkpoint blockade and T cell redirecting bispecifics. In addition, data from new classes of targeted immuno-therapies in preclinical development will be discussed.

With the majority of patients relapsing after multiple lines of diverse treatments, multiple myeloma remains a largely incurable disease. Here we profile a novel GPRC5DxCD3 T cell-engaging bispecific antibody with a unique 2:1 IgG-like antibody format conferring antigen avidity and extended half-life. We demonstrate superior potency and efficacy of our 2:1 antibody format in patient-derived allogeneic and autologous T cell co-cultures and in tumor-bearing humanized mouse models.

Neo-X-Prime is a platform based on bispecific conditional CD40 agonistic antibodies that target TAAs expressed at high densities, where the lead program, ATOR-4066, targets CD40 and CEA. We have demonstrated that Neo-X-Prime bsAbs enable a novel mode of action involving delivery of tumor antigens to DCs and increased priming of tumor-specific T cells, which results in increased anti-tumor efficacy compared to monoclonal antibodies.

MAIT cells are an abundant, tissue and tumor-resident cytotoxic T cell subset that possess a unique T cell receptor (TCR). BiXAb-mediated engagement of MAITs (via the unique TCR) and a cancer cell (via a tumor-associated antigen) leads to efficient killing of the tumor cells. This modality does not induce activation of general T cell subsets, in contrast to classical T cell engagers, and promises to significantly impact solid tumors.

T cell activation requires strong TCR engagement, co-stimulation, and cytokines to promote activation, differentiation, and proliferation. Many tumors lack the signals necessary to promote robust activity with existing immune therapies. This presentation will describe preclinical data on combinations of CD28 co-stimulation, checkpoint blockade, T cell redirecting bi-specifics and cytokines to enhance anti-tumor efficacy of immune-oncology therapies. Data will be presented on engineering criteria for improved therapeutic index and efficacy.

Antibody-based immunotherapy is a promising strategy in cancer treatment. IgG eliminates tumor cells through NK cell-mediated ADCC and macrophage-mediated antibody-dependent phagocytosis. Neutrophils have been largely overlooked as potential effector cells, because IgG ineffectively recruits neutrophils. Bispecific antibodies, which potently activate neutrophils and induce migration through FcaRI have been developed. Coupling of TNFa further recruits neutrophils as effector cells, which will be discussed.

• Recruitment of neutrophils for tumor therapy​
• Targeting the IgA Fc receptor CD89
• Boosting the immune system with TNF-a

Cytokines emerged as promising molecules for therapeutic intervention in order to modulate the immune response. However, their often pleiotropic nature combined with their high potency when administered systemically restricts their therapeutic applicability. We have generated cytokine mimetics with tailor-made mode-of-actions based on multifunctional antibody derivatives.

Besides classical mAbs, bispecific and multi-specific antibodies promise to be more efficacious in certain therapeutic settings since they can modulate more than one disease mediator. However, the generation of these antibodies requires extensive engineering. We have established different platforms to generate antibodies with up to four specificities. In addition, we were able to demonstrate NK-cell redirection with each format.

Despite recent advances in the field of non-Hodgkin lymphoma (NHL), relapsed/refractory NHL remains a challenge. T cell exhaustion contributes to treatment failure following T-cell redirecting immunotherapeutic approaches. To overcome this issue, we developed a first-in-class trispecific antibody that simultaneously engages CD19 on tumor cells, CD3 and CD2 on T cells, leading to redirected T cell cytotoxicity towards CD19-positive malignant B cells with more favorable and durable T cell activation.

• Pre-clinical models (in vitro and in vivo) to support discovery and development
• Reentering the fray with costimulatory agonists
• Clinical development strategies for combinations with immune cell engagers​

Tumor-targeted CD28 bispecific antibodies (bsAbs) enable T cells costimulation in a TAA-dependent manner. We generated an array of TAA-CD28 κλ bodies targeting different tumors that enhance the antitumor response induced by T cell engagers (TCE) via the induction of T cell proliferation and activation, increased cytokine secretion and boosted anti-tumoral cytotoxicity. In vitro and in vivo data highlighting how CD28 bsAbs synergize with TCEs will be presented.

MCLA-145 is a Biclonics T cell agonist that binds with high affinity and specificity to human PD-L1 and CD137. MCLA-145 drives transactivation of CD137 in the vicinity of cells expressing PD-L1, such as in the immunosuppressive tumor microenvironment. MCLA-145 shows enhanced T cell priming and can promote long-term T cell immunity. In vivo, MCLA-145 demonstrates anti-tumor activity superior to the current standard immune checkpoint inhibitor comparators.

Marengo Therapeutics has pioneered a novel antibody-based platform to modulate T cells through targeting germline-encoded beta chain variant of the TCR and therefore targets T cell subsets with distinct reactivities. Incorporating this technology into various bispecific formats supports therapeutic T cell activation and redirection for cancer immunotherapy as well as applications in other disease areas. Marengo's lead program, STAR0602, is a bispecific fusion molecule combining a novel mode of TCR activation with co-stimulation to support pan-tumor therapy for antigen rich tumors.