Recent approvals of radiopharmaceuticals for prostate and neuroendocrine cancers have renewed interest in antibodies for targeted radionuclide therapy. Advantages include the potential for paired imaging to evaluate target expression, delivery and response to radioimmunotherapy (“theranostics”); disadvantages include extended circulation of antibodies leading to hematologic toxicity. PK-optimized engineered antibodies and fragments can provide novel agents for non-invasive imaging (of tumors and immune cells) and localized delivery of therapeutic radionuclides.

Radiopharmaceutical therapy can be used to deliver radiation to tumor sites throughout a patient’s body in settings of metastatic disease while minimizing dose to healthy tissue. Radiopharmaceuticals can elicit immunogenic tumor cell death and phenotypic changes in surviving tumor cells as well as inflammatory changes in the tumor microenvironment, and this may alter tumor immunogenicity in a way that enables cooperative therapeutic effects in combination with certain immunotherapies. Further preclinical and clinical research is needed to clarify mechanisms whereby radiopharmaceutical therapies may affect anti-tumor immunity and response to cancer immunotherapies.

By ablating all disease-associated functions of a given protein at once, targeted protein degradation has emerged as a promising therapeutic strategy to overcome limitations of traditional occupancy-based inhibitors To this end, at EpiBiologics, we are developing three fully recombinant and modular bispecific antibody-based platforms—AbTACs, KineTACs, & TrainTACs—that can be applied to effectively mediate degradation of cell-surface and extracellular proteins.

Cytokines coordinate all facets of immune biology and thus harbor great therapeutic potential. However, endogenous cytokines are poorly suited as drugs due to their pleiotropy and poor pharmacological properties. Complexing cytokines with anti-cytokine antibodies enhances their specificity and developability, but translating a mixed cytokine/antibody complex is impeded by stability concerns. We overcame these limitations by engineering single-agent cytokine/antibody fusion proteins (immunocytokines) that bias the immune response for various disease applications.

Anti-PD-1 antibodies demonstrate strong cPOC, but innate/acquired resistance remains a major challenge. Fusion of cytokines including IL-2 /IL-15 variants to anti-PD-1 enhances the activity of antigen-experienced T cells enriched for tumor specificity but the nature and/or potency of the cytokine negates checkpoint inhibition due to toxicity—and can drive terminal exhaustion. We engineered IL-1BP resistant/IL-18 variants attenuated >10,000 fold that can be dosed safely to levels consistent with checkpoint inhibition and regain IL-18 activity when bound to PD-1+/IL-18R+ T cells to preserve/augment CD8+ PD1+ TpEX, both enriched for tumor specificity and directly responsible for the therapeutic effect of PD-1 antagonism.

Antibody-cytokine conjugates leverage orthogonal mechanisms of action (MoA) in one molecule to induce potent antitumor immune responses. At Bright Peak, we generate immunocytokines through site-specific chemical conjugation of cytokine to “off-the-shelf” human IgG antibodies. During the talk, I will focus on our PD-1-targeting conjugates and share compelling preclinical data supporting the future development of BPT567, a PD1-IL18 immunocytokine.

Downregulation of targets limits the efficacy of monotargeted T cell engagers (TCE). ISB 2001, a first-in-class TCE targeting both CD38 and BCMA, demonstrated superior tumor cytotoxicity in vitro, in vivo, and ex vivo using patient samples when compared to teclistamab. Clinically, ISB 2001 demonstrated an overall response rate of 75% across all dose levels and a favorable safety and tolerability profile in heavily pretreated patients with r/r MM.

Vγ9Vδ2-T cells constitute a relatively homogeneous population of pro-inflammatory immune effector cells. This presentation will focus on the preclinical and early clinical development of bispecificVγ9Vδ2-T cell engagers as a novel approach for cancer immunotherapy.

T cells require T cell receptor engagement by peptide-major histocompatibility complexes coupled with CD28-mediated costimulation for optimal activation. Tumor cells typically lack expression of CD28 ligands, so we hypothesized that CD28 signaling at the T cell/tumor cell interface could enhance anti-tumor activity. We generated tumor-associated antigen (TAA) x CD28 bispecific antibodies that provide CD28 costimulation only in the presence of TAA and TCR engagement and show enhanced activity over traditional bispecifics.

The first-in-class bispecific antibody IMV-M, targets MUC16 and death receptor 5. It is uniquely designed to cluster DR5 effectively, but only in MUC16-positive cancer cells, directly activating apoptosis to induce cancer cell death. This mechanism differentiates IMV-M from ADCs, which rely on cytotoxic drugs, and from bispecific immune cell engagers. IMV-M offers the advantage of avoiding resistance to chemotherapy and reducing the side effects associated with these therapies. IMV-M has demonstrated potent efficacy in various xenograft cancer models and shown safety in non-human primates.