We created novel fully human dual-specific antibodies that both block both PD-L1 and PD-L2 with high affinity and target PD-Ligand cells for depletion via ADCC and ADCP. The lead antibody outperforms PD-1 blockade across both "hot" and "cold" cancers through a unique combination of stromal depletion, complete PD-1 circuit blockade, and direct anti-tumor cytolysis. These antibodies appear safe in both mice and primates are moving into Phase I.

Regulatory T (Treg) cells represent a major immunosuppressive cell type in tumors and targeted depletion of tumor resident Treg cells can be a promising therapeutic approach to restore anti-tumor immunity. We have developed a human IgG1 antibody to preferentially eliminate CCR8-expressing Treg cells in tumor microenvironment through ADCC. The preclinical PK/PD findings and the methods used for translation to the clinic, including the selection of First-in-Human (FiH) dose, to inform the Phase I study design will be presented. 

We have developed an antibody which binds to tumor-associated LYPD3 in an O-glycosylationdependent manner and shows superior tumor specificity compared to conventional protein-binding anti-LYPD3 antibodies. The specificity of our antibody for glycosylated LYPD3 was determined using differentially glycosylated proteins in an ELISA format and confirmed using cell lines with specific glycosylation patterns as well as tumor cell lines expressing varying levels of LYPD3. Furthermore, binding to healthy and tumor tissues was analyzed by immunohistochemistry.

• ​What makes a target particularly difficult?
• How to evaluate the challenges
• Selection of therapeutic modality
• Selection of optimal discovery strategy
• Screening alternatives
  

• ​Mechanisms of action of TNFRSF agonistic antibodies
• Lessons learned in the clinic
• FcγR2B and tumor targeted conditional agonisms
• New clinical developments to watch
  

INBRX-109 is a precisely engineered tetravalent agonist of death receptor 5. Designed to achieve a best-in-class therapeutic index, INBRX-109 induces robust apoptosis of cancer cells in vitro and in vivo while sparing healthy tissues. INBRX-109 was well tolerated and had anti-tumor activity in unresectable/metastatic conventional chondrosarcoma in a phase I study and is currently being evaluated in a blinded, placebo-controlled pivotal phase II trial.

Redirecting preexisting virus-specific cytotoxic CD8+ T lymphocytes (CTLs) to tumors by simulating viral infection of the tumor cells has great potential for cancer immunotherapy. In this talk, I will present a CTL epitope-delivering antibody, termed a TEDbody, engineered to deliver a viral MHC-I epitope peptide into the cytosol of target tumor cells by fusion with a tumor-specific cytosol-penetrating antibody for the recognition and lysis by virus-specific CTLs.

Complete remissions in hairy cell leukemia (HCL) with anti-CD22 recombinant immunotoxin Moxetumomab Pasudotox (Moxe) are more durable if minimal residual disease (MRD) negative, but anti-drug antibodies (ADA) can limit the effectiveness of the consolidation cycles needed to eliminate MRD.   To prevent ADA, Rituximab or Ruxience was added to Moxe (MoxeR) and 9 (64%) of 14 evaluable patients so far achieved MRD-free CR. ADA was less frequent than Moxe alone historically.

Donor NK cells can induce complete remissions in patients with refractory leukemia. However, limitations include lack of persistence and specificity. Off-the-shelf NK cells from induced pluripotent stem cells (iPSC) containing multiple gene edits will promote specificity, persistence, and enhanced activity in vivo to enhance cancer therapy. While Chimeric Antigen Receptors (CARs) are best validated in B cell malignancies, strategies targeting B7-H3 in solid tumors will be discussed.

Interleukin-2 (IL-2) potently stimulates the proliferation, survival, and cytotoxicity of T and NK cells making it an attractive candidate for cancer immunotherapy. However, severe toxicities have limited its clinical utility. We have developed STK-012, an IL-2-agonist mutein selective for cells expressing the high affinity, trimeric IL-2 receptor (IL-2Ra/b/g) such as activated T cells. STK-012 preferentially stimulates tumor-specific T cells without significantly activating NK cells thus facilitating prolonged treatment without acute toxicity.

IL-18 is a pro-inflammatory cytokine that promotes CD8+ T cell and NK cell effector function, enhancing intratumoral cytotoxicity. To date, clinical trials of recombinant IL-18 have demonstrated safety, but a lack of efficacy alone, or in combination with anti-cancer agents. The wild-type cytokine is challenging to produce, unstable, and cleared rapidly from circulation. We engineered a stabilized, half-life extended version of IL-18 and will be sharing pre-clinical in vivo results.

XPAT proteins are conditionally active T cell engagers (TCEs) designed to exploit the dysregulated protease activity in tumors. In preclinical studies across multiple tumor targets, XPAT proteins demonstrated 1) strong masking of in vitro cytotoxicity by up to 4 logs; 2) potent in vivo efficacy at doses similar to the efficacious doses of unmasked TCE controls; and 3) masking increases tolerated Cmax in NHP by greater than 400-fold for HER2-XPAT.

The ability to bridge the innate and adaptive arms of the immune system coupled with their capacity to recognize tumor cells independent of MHC makes gamma delta T cells an attractive target for cancer immunotherapy. The engineering and therapeutic potential of a butyrophilin 2A1 and 3A1 protein-based engager platform (GADLEN) that offers a novel approach to activate the Vg9Vd2 T cell subset for targeted killing of tumor cells will be presented.