We present preclinical data on NBE-002, a novel ROR1-targeting ADC based on Sortase A-mediated, site-specific conjugation of a derivative of the highly potent anthracycline PNU-159682. NBE-002 is a highly effective and promising targeted therapeutic for the treatment of ROR1-positive TNBC and other solid tumor indications and is currently in clinical development. Due to the pronounced immune-modulatory functions of the PNU payload, NBE-002 is particularly well suited for combination therapy with immune checkpoint inhibitors.

Antibody-Targeted Amanitin-Conjugates (ATACs) introduce a new mode of action into oncology therapy. The inhibition of RNA polymerase II facilitates killing of dormant tumor cells (CSCs, TICs) and offers new treatment options for difficult to treat cancers and high-risk patients. The unique MoA in combination with a demonstrated safety profile and a biomarker for patient selection might pave the way for accelerated development & approval for patient groups with high therapeutic needs. HDP-101 is a BCMA-ATAC entering Phase I trials for Multiple Myeloma in 2021.

Mirvetuximab soravtansine, our first generation FRa-targeting ADC is in two phase III studies, MIRASOL and SORAYA, in patients with platinum-resistant epithelial ovarian cancer with high levels of FRa. To address the unmet need of additional patient populations, we developed a next-generation anti-FRa ADC, IMGN151, which is active against tumors with a broader range of FRa expression. IMGN151’s innovative design, including the biparatopic antibody, and favorable preclinical activity will be presented.

SMARTag is a clinical-stage ADC technology featuring site-specific conjugation with multiple linker and warhead options. TRPH-222, a CD22-targeted SMARTag conjugate in the dose-escalation stage of a Phase 1 trial for R/R B-cell lymphoma, has achieved 6 CRs and 2 PRs among 22 patients to date.  In addition to site-specific conjugation, we have developed new linkers to achieve proprietary high DAR ADCs featuring topoisomerase I inhibitor payloads. 

TGF-b is one of the most immuno-suppressive cytokines in virtually all solid tumors. Despite long standing interesting in TGF-b therapies for cancer patients, systemic TGF-b have had limited success, since they cause severe toxicity, particularly in the heart. Synthis is an early stage biotech company, developing a first in class, cell-targeted therapeutic platform that selectively reverses TGF-b mediated immune suppression to safely drive tumor clearance.

This talk will summarize learnings from stromal targeting antibody-drug conjugates both preclinically and clinically. Findings from ABBV-085 which targets the stromal antigen LRRC15 which is highly expressed on cancer associated fibroblasts (CAFs) in the tumor microenvironment, will be discussed. Preclinical and Phase 1 findings will be summarized, with a view to highlighting challenges and opportunities for targeting stromal antigens with antibody-drug conjugates.

Nuclear-Delivered Antibody-Drug Conjugates^TM (ND-ADCs) are a novel form of ADC which benefit from direct internalization of the ADC to the nucleus, utilizing a unique biology of the endothelial transport protein TM4SF1. Through nuclear delivery via microtubule in both tumor cell and tumor endothelium, AGX101 has demonstrated excellent tumor regression efficacy and safety in preclinical animal models. AGX101 awaits for Phase 1 clinical trial in late 2021.

We designed Immunosynthen, a novel STING agonist antibody-drug conjugate platform ideally suited for systemic administration of STING agonists with reduced toxicity. XMT-2056, an Immunosynthen-based tumor antigen-targeted STING agonist ADC exhibits excellent drug-like properties and >100-fold increased potency as compared to the free STING agonist. In mice, XMT-2056 induced robust anti-tumor immune activity, with only minimal increases in systemic cytokine levels. XMT-2056 is well-tolerated in non-human primates, and the ADC exhibits favorable pharmacokinetics after repeat doses. Together these data support the clinical development of XMT-2056.

We envisioned a preferential activation of ADCs in tumor versus healthy tissues to improve the therapeutic window. Towards this goal we developed ADCs with novel linkers which are efficiently and selectively cleaved by the tumor-associated protease legumain. A remarkable tolerability of legumain for different linker peptides together with a modifier of the physicochemical catabolite profile allow for a tailored design of ADCs for different targets.

Clinical efficacy of ADC products is hindered by their slow and inefficient accumulation in solid tumors. Small molecule-drug conjugates (SMDCs) have been recently proposed as an alternative approach to effectively deliver potent cytotoxic compounds to the neoplastic site and to solid metastatic lesions. We are developing SMDC products to target potent anti-tubulin poisons to solid tumors expressing CAIX and FAP.

Despite major advances in antibody-drug conjugate (ADC) technology, dose-limiting toxicities that limit therapeutic efficacy are frequently observed. We have engineered the antibody component of a HER2-specific ADC to result in more efficient lysosomal delivery following internalization into cells. The engineered ADC (ALTA, for ADC with increased Lysosomal Trafficking Activity) is expected to lead to reduced off-tumor toxicities by enabling the use of lower doses.

There continues to be a need for new ADC linker strategies for the lysosomal release of payloads. We have undertaken an effort to prepare and screen a peptide library for new cleavable linkers. We will describe new legumain-cleavable linkers that we have identified from this work – and will also report preliminary work for the optimization of new self-immolative spacers for the release of alcohols and anilines.