To improve the clinical success of ADCs, it is critical to have adequate translation of preclinical TI (a measure of safety and efficacy) to clinical TI. However, the translation of the TI has been limited by the choice of preclinical models and their relevance for human patients.  

• Limitation of preclinical tumor models to evaluate ADC efficacy and immuno-oncology combination therapeutics
• Utility of innovative in vitro tumor organoids and other models in improving TI prediction
• Limitation of preclinical NHP toxicology models to predict delayed toxicities 
• Mechanistic in vitro toxicity models that can improve TI prediction 

Conjugation of linker-payloads to the antibody glycan (GlycoConnect) together with a polar linker (HydraSpace) provides ADC with significantly improved TI. By combination with the potent TOP1i exatecan (SYNtecan E), ADCs are generated that induce complete and durable tumor regression in multiple in vivo mouse models, with excellent tolerability in non-human primates. Highlights include:

• strong additive effect of SYNtecan E by combination with checkpoint or PARP inhibitors
  
• immunogenic cell death confirmed in vivo and in vivo, no tumor regrowth upon rechallenge in syngeneic models
• data to be presented on SYNtecan E ADCs from multiple preclinical and clinical programs
  

MYTX-011 is an investigational, pH-sensitive, vcMMAE ADC. It has been designed to benefit a broader population of patients whose tumors express lower/moderate levels of cMET as compared to other cMET ADCs, which have shown clinical activity only in patients whose tumors express high levels of cMET. MYTX-011 drives increased internalization and cytotoxicity and shows robust activity in xenograft models across a range of indications and levels of cMET expression.

This study examined the biophysical properties of the antibody-drug-conjugate (ADC) MORAb-202, a humanized anti-folate receptor alpha (FRa) antibody conjugated with maleimido-PEG2-val-cit-pAB-eribulin through partially-reduced interchain disulfide bonds with an average drug-to-antibody (DAR) of 4.0 and a DAR range of 0 to 8. Isolated DAR species of MORAb-202 demonstrated a DAR-dependent loss of FcgR and C1q binding and associated effector activity, with no loss of antigen or FcRn binding.

Small-molecule therapeutics are sometimes limited by toxicity, pharmacokinetics, or cell permeability. Antibody-drug conjugates or ADCs offer the targeted delivery of small molecules that can mitigate such liabilities. This talk will focus on our efforts to link chimeric protein degraders (PROTACs) to antibodies, their efficacy and safety, and how this general approach can expand the utility of directed protein degradation as both a biological tool and a therapeutic possibility.

The Affilin targeting platform is continuing to accumulate data differentiating it from other targeting approaches including antibodies and antibody fragments. Affilin candidates across different targets show consistently high and long tumor accumulation and outperform benchmarks especially in low expressing tumor models. At the same time the exceptional modularity of the platform allows quick cycle times and designing multiple format types including bi and multispecific targeting ligands with ease.

We will describe our efforts to understand the efficacy of TLR7 agonist-antibody conjugates, focusing on correlating in vitro assays with in vivo efficacy. We will describe the impact of Fc-gamma binding, linker type, and payload potency on the functional activity, efficacy, and PK of the resulting conjugate.

Synthis Therapeutics is a NY biotech company developing the next generation of immunomodulatory antibody-drug conjugates (ADCs) for cancer patients. Comprised of an immune cell targeted antibody attached to a non-cytotoxic payload, SYN101 is a first-in-class ADC that selectively and safely blocks immune suppression and drives tumor clearance, in multiple tumor models in vivo. We are raising a $35M Series A for IND enabling and Phase I trials.

This presentation will navigate the complexities of OBT076, an innovative ADC with dual mechanisms of action, providing detailed insights into its design, preclinical activity, and the latest clinical advancements in Phase 1 trials.

Tubulis’ versatile ADC technology suite will be introduced, including:

• Tubutecan (Topo-I) DAR8 platform with long-lasting efficacy profile, mAb-like PK properties, and no premature payload loss
• Tubutecan-based lead molecules TUB-040 and TUB-030 will be highlighted
• Alco5, a novel linker enabling easy access to OH-containing compounds to unlock previously unprecedented ADC payloads?​

Current clinical-stage ADCs utilize a narrow range of payloads. The majority of patients on ADCs will progress, with payload resistance being of key concern. Furthermore, there has been limited clinical validation for payloads with novel modes-of-action. Combination of small molecule cytotoxic agents has shown promise, improving clinical efficacy. However, the untargeted, systemic therapy approach leads potentially to therapeutic window limitations. Combination of two small molecule payloads in an ADC presents a targeted, single agent approach to optimize their potential and improve the therapeutic window.

This presentation will discuss the unique features of VIP943, a groundbreaking CD123-targeted ADC with a KSPi payload, cleaved by Legumain for precise and effective treatment of CD123+ hematological malignancies. This presentation elucidates the therapeutic potential and innovative design strategies behind VIP943.

We have designed an ADC class using a novel self-immolative T moiety for traceless conjugation and release of exatecan, a more potent topoisomerase I inhibitor with less sensitivity to multidrug resistance (MDR). T moiety-exatecan ADCs showed higher stability, enhanced efficacy, and greater tolerability in preclinical testing across multiple programs.  The development rationale and clinical progression of T moiety exatecan ADCs targeting known and novel tumor antigens will be discussed.

ADCs have failed in gastrointestinal tumors due to critical limitations. Immunoglobulins dominate the industry, however, antibody fragments may have advantages including rapid tumor penetration, faster clearance, inexpensive manufacture, but have been technologically challenging to apply in oncology. Antikor’s lead ANT-045 is highly stable and demonstrates excellent tumor ablation in gastric cancer models with high/medium/low cMET receptor-levels as low as 8000/cell. Recently we showed ANT-045 is exceptionally well tolerated in cynomolgus-primates at doses of 2mg/kg (~20mg/kg for an ADC) showing none of the dose-limiting hematological toxicities associated with ADCs. A TI exceeding 32 is predicted making ANT-045 a promising new therapy.

Avibodies (enhanced diabodies) comprise unique surface disulphides for precise loading of drug payloads (auristatins) with superior tumor xenograft regression compared to conventional IgGs (anti-CD30). PK of Tag-72 targeted Avibodies was demonstrated in a first-in-human Phase 1 clinical biodistribution trial. With TagWorks, Avibodies were shown to pre-target and upload tumors with the ADC-drug subsequently released by a systemic activator. Avipep’s novel Avibody designs demonstrate precise site-specific loading of drug payloads.