In this talk, we will discuss next-generation bispecifics biologics, including IgG antibody, BiTE, CAR T cells, CD-3 T cells and enhanced TCR-based bispecifics. We’ll continue into the clinical landscape of bispecifics and learnings from the successful and failed bispecifics, as well as combinations biologics, and whether we should consider them friends or foes.

REGN4018 binds both MUC16 and CD3. REGN4018 inhibited growth of human tumors in a xenogenic model and murine tumors expressing human MUC16. Combination with an anti-PD-1 antibody enhanced this efficacy. Immuno-PET imaging demonstrated localization of REGN4018 in MUC16-expressing tumors, as well as in T cell-rich organs. Toxicology studies in cynomolgus monkeys showed minimal and transient increases in serum cytokines, and C-reactive protein following REGN4018 administration with no overt toxicity.

This talk will dive into an investigation of co-expression of multiple immune checkpoint receptors by tumor-infiltrating lymphocytes, whose co-blockade provides additional benefits in immunotherapy. We will also discuss selection and format optimization of bispecific molecules for simultaneous blockade of two checkpoint pathways, in addition to discussing MGD013 and MGD019 preclinical pharmacology, IND enabling studies and clinical trial design.

In this talk, we will share comprehensive clinical experience gained from interim analyses of the PRS-343 trials, and provide an overview about the broader Pieris pipeline of 4-1BB targeting antibody-anticalin bispecific molecules.

Antibodies blocking the PD-1 signaling pathway has led to a tremendous effort in combinations and bispecifics to further improve outcomes in cancer. CD27 is a costimulatory molecule providing a complementary target to the PD-1/PD-L1 axis on T cells. A tetravalent format was selected for CDX-527, that along with potent PD-1 blockade, provides efficient cross-linking, which is important for CD27 agonistic activity by allowing interaction with both Fc-receptor and PD-L1-bearing cells.

The Siglec/sialoglycan axis has recently emerged as a new mechanism of cancer immune evasion. We engineered a human sialidase and developed a bifunctional antibody-sialidase platform named EAGLE to inhibit this axis. EAGLE showed enzyme-dependent, robust monotherapy efficacy with complete regressions and immune memory in preclinical tumor models. We further demonstrated EAGLE’s mechanism of modulating innate and adaptive antitumor responses, and identified correlative pharmacodynamic biomarkers to EAGLE treatment in preclinical models.

Landmark advances in the engineering and development of bsAbs are enabling unprecedented versatility in therapeutic antibody concepts. Currently more than 20 different commercialized technology platforms are available for bsAb creation and development, two bsAbs are marketed and over 85 are in clinical development. A defining bsAb feature is their potential for novel functionalities – that is, activities that do not exist in mixtures of the parental or reference antibodies. This presentation will provide insights in the design and function of these so-called obligate bsAb and their potential in drug development.

Oncolytic viruses replicate and induce lymphocyte infiltration in tumors. However, the infiltrating T cells target exclusively virus-infected cells due to the immunodominance of viral antigens. BiTEs and BiKEs secreted from the oncolytic virus offer a unique opportunity to retarget T cells or NKs towards non-infected bystander tumor or stromal cells. Further, selective expression in tumors reduces the potential systemic toxicity of these engagers. Results on this strategy will be presented.

Farletuzumab, an ADCC-activating, humanized antibody targeted against folate receptor alpha-1 (FOLR1), improves survival advantage for a very small subset of ovarian cancer patients having low cancer antigen-125 levels. Since a larger ovarian cancer population highly overexpresses cancer antigen-125, we argue that ADCC-based approaches are not clinically feasible options. Therefore, to achieve a clinically applicable and patient-centered approach, we hypothesize enhancing farletuzumab’s anti-tumor activity beyond and independent of the ADCC function. One such approach is epithelial cancer-enriched death receptor 5 (DR5/TRAIL-R2) activating antibodies. TRAIL-R2 is a major extrinsic apoptotic pathway receptor expressed in tumors of epithelial origin, and we have engineered, tested and characterized a novel bispecific-anchored Cytotoxicity-activator (BaCa) antibody that combines the specificities against the FOLR1 and TRAIL-R2. In our preliminary studies, the BaCa antibody not only generated an exceedingly oligomerized and activated TRAIL-R2 receptor complex, but also induced a very high level of apoptosis that is remarkably selective to ovarian cancer cells and tumors. Importantly, the cytotoxic function of the BaCa antibody is self-sufficient, and does not require selective infiltration and ADCC activity of immune effector NK cells or cytotoxic signaling of T cells into the tumors. Our studies strongly support the high in vivo activity of BaCa antibody in tumor xenografts, as well as in patient-derived cell lines compared to clinically failed antibodies. Since extrinsic TRAIL-R2-induced cell death is independent of intrinsic p53-mediated apoptosis, our data also supports a tailored treatment strategy for the majority of serous ovarian carcinomas (>90%) harboring p53 loss-of-function mutations. In summary, the described BaCa antibody strategy represents a “moonshot strategy” to generate effective therapy for advanced-stage serous adenocarcinoma patients without the intervention of immune effector cells. If successful, this approach will significantly improve the survival of ovarian cancer patients with desirable clinical safety.

One of the effective approaches to improving the outcome of CAR T cell therapies is by targeting multiple tumor-associated antigens (TAA). To address current drawbacks in achieving multiple-tumor targeting using scFvs, we used single-domain antibody mimics with small size, simple structure, and high stability that can be modularly engineered on the surface of immune cells to acquire multifunctional TAA recognition. We demonstrated that protein domains targeting EGFR and HER2 of the ErbB family can be assembled into antibody mimic receptor (amR) molecules, and efficiently redirect T cells for biepitopic or bispecific TAA recognition in vitro and in vivo.

Safe and selective blockade of the innate immune checkpoint CD47 can be achieved using bispecific antibodies (bsAb) having two arms with different affinities. This dual targeting concept has been validated in different preclinical models of human cancer and is now being explored in patients with a bsAb generated using our kappa-lambda body platform.