Antigen-Targeted Amanitin-Conjugates (ATACs) represent a new class of ADCs using the payload Amanitin. This payload introduces a novel mode of action into oncology therapy, the inhibition of RNA polymerase II. The technology platform includes Amanitin supply, site-specific conjugation, demonstrated safety profile and biomarker. HDP-101 is the first ATAC directed against BCMA soon entering Phase I trials.

Avibodies^TM comprise unique surface disulphides for precise loading of drug payloads (auristatins, maytansinoids) with superior tumor xenograft regression compared to conventional IgGs (targeting CD30). PK of Tag-72 targeted diabodies has been demonstrated in a first-in-man Phase 1 clinical biodistribution trial. With TagWorks NV², Avibodies were shown to pre-target and upload tumors with the ADC-drug subsequently released by a systemic activator.  In summary, Avipep’s novel Avibody^TM designs enable precise site-specific loading of drug and isotope payloads for cancer imaging and ADC therapy.

Antibody Drug Conjugates (ADCs) are an emerging class of therapeutics offering the opportunity to develop truly targeted therapies, facilitating release at the point of treatment, by attaching cytotoxic drugs to an antibody using a linker. However, developing and manufacturing ADCs can be a complex process.

By combining our anti-PD-L1 Affimer antagonist (AVA04 Fc) with a potent, small-molecule inducer of the innate immune system (Val-Boro-Pro, VbP), we have demonstrated full tumour regression in mouse syngeneic models with an immunological memory effect in several individuals. We have developed an Affimer-drug conjugate (TMAC) that included a novel FAP-a cleavable linker which is preferentially cleaved in the TME, which showed significant anti-tumour effects in a CT26 syngeneic model and reduced the toxicity profile for VbP. 

“Hydrophobicity masking” chemical modifiers can be orthogonally embedded into drug-linker constructs of ADCs. These hydrophilic entities have the potential to enable increased drug-loading (drug-antibody ratios at or above 8) and improve PK profiles, efficacy, and tolerability of ADCs. Our efforts in developing a hydrophilic, monodisperse, polysarcosine-based ADC platform will be presented. Impact of polysarcosine on physicochemical and pharmacological properties of conjugates bearing different payloads will be discussed.

Duotoxins combine Fab-Pseudomonas, exotoxin-based immunotoxins, plus DM1 on one molecule. The molecules aim to generate high in vivo specific Synergy as two highly synergistic molecules are combined on one antibody fragment.

We will introduce a new linker antibody-conjugation technology that enables site-specific payload attachment to native antibodies ‘off-the-shelf’ in one or two steps without prior engineering. We will show that our linkers enable the incorporation of various functional chemistries and a loading of 2 or 4 in one ADC. We found that the resulting ADCs have favorable physicochemical properties and showed very efficient anti-tumor responses in head-to-head efficacy studies compared to conventional ADCs using the same antibody and payload.

Antibody-drug conjugates (ADCs) and small-molecule drug conjugates (SMDCs) represent two conceptually related strategies for the targeted delivery of potent cytotoxic agents to various types of cancer. In this lecture, I will present a comparative analysis of therapy and biodistribution results in mouse models of cancer, as well as clinical data and information on how ADCs and SMDCs can be potentiated using targeted cytokine therapeutics.