Designed Ankyrin Repeat Proteins (DARPins) offer distinct advantages for therapeutic drug design, including small size, thermostable architecture, and high target specificity and affinity. This presentation highlights recent advances of our Radio-DARPin Therapeutics (RDT) program. Through surface engineering and half-life tuning, we developed RDT candidates with minimal kidney accumulation and effective tumour uptake. Thereby, they exhibit biodistribution properties suitable for therapeutic applications and overcome nephrotoxicity-related limitations of other protein-based radiopharmaceutical approaches.

HER2 is an oncogenic driver of several cancers. An affibody molecule specific for HER2 has been developed. Receptor expression levels in metastatic lesions in patients with spread disease can be determined using PET imaging. Tissue distribution profile has been optimised for therapy by protein engineering. Preclinical data show potential for therapeutic effect in combination with trastuzumab. ABY-271 is in preclinical development for molecular radiotherapy of patients with HER2-expressing disease.

Elimination of extracellular proteins is a compelling therapeutic modality. EpiTACs are bispecific antibodies in which one arm binds a target and the other arm leverages an EpiAtlas of tissue-enriched degrading receptors comprised of transmembrane ligases, cytokine/chemokine receptors, and internalizing receptors resulting in selective degradation of membrane and soluble proteins. EpiTACs elicit robust in vitro and in vivo activity in a target-, tissue-, and disease-specific manner for a broad range of indications. Compelling data with EGFR demonstrates that EpiTACs can degrade a target independent of mutational status, are better than SOC in preclinical models, and in vivo drive a survival benefit in tumour models.

Antibody Drug Conjugates (ADCs) have proven to be a very successful modality. Their therapeutic potential is, however, limited by off-tumour toxicity associated with the (free) payload. Recently, an innovative class of small molecules has drawn attention for use as novel payloads: heterobifunctional protein degraders. During this presentation we will show how the sophisticated design of these novel degrader-based payloads can overcome these challenges and improve the therapeutic window of ADCs.

Delivery of therapeutics to the brain remains a significant challenge. Ossianix developed TXP1, a brain shuttle based on a single-domain anti-TfR1 antibody, with reactivity to human and monkey. In NHPs, TXP1 exhibited >35-fold increase in brain penetration, distributed widely in the brain but without accumulation in other organs. TXP1 represents a technological leap forward in achieving high brain-penetration and specificity, holding promise for patients with CNS disorders.

Brain uptake of therapeutic modalities such as antibodies and recombinant enzymes is severely limited by their size due to the blood brain barrier (BBB). To address this issue, we are developing technologies to actively transport these molecules across the BBB using receptor-mediated transcytosis. Our BrainTransporter (BT) platform technology is engineered using structural data as guidance to engage with a BBB receptor in a preferable position. Currently, the BT system is applied with the goal to improve the treatment of various brain disorders.

• Anti-cancer antibody-based therapeutics suffer from several limitations, including immunogenicity, high cost-of-goods, and slow extravasation rate in solid neoplastic lesions
• Small molecule therapeutics such as Small Molecule-Drug Conjugates (SMDCs) and Radio Ligand Therapeutics (RLTs) have been proposed as an alternative to antibody-based therapeutics
  
• The DEL technology (DNA-Encoded Chemical Libraries) is an effective ligand discovery tool. DEL-derived ligand can be equipped with therapeutics radionuclides or with cytotoxic drugs to generate RLTs or SMDCs.
  
• In this talk, the generation and in vivo characterization of DEL-derived anti-cancer small molecule therapeutics will be presented.
  

The high prevalence of non-canonical disulfide bond between CDRH1 (C35a) and CDRH2 (C50) in rabbit antibodies poses significant challenges for therapeutic development, particularly in terms of stability. In my presentation, I will delve into the topics of developability, functionality, and structural insights regarding its role. Additionally, I will discuss engineering solutions, including structure- and ML-guided optimization strategies, focusing on how we address this disulfide bond in our newly-discovered cross-reactive anti-PD-1 rabbit antibodies. The comprehensive assessments aim to overcome the hurdles posed by this disulfide bond and enhance the therapeutic potential of this group of antibodies.

Introducing Inno8, a pioneering oral Factor VIII (FVIII)-mimetic haemophilia drug candidate based on VHH modality. Developed through innovative engineering, Inno8 offers unprecedented FVIII co-factor mimicking activity, with improved pharmacokinetics and oral bioavailability as a breakthrough invention. Thus, this first-in-class antibody-based oral drug modality presents a transformative approach, not only potentially reshaping the standard of care for haemophilia A patients, but also offering promise for a range of chronic diseases.