Leadartis

Leadartis is a preclinical stage immuno-oncology company engaged in the development of TrimerobdyTM, a novel class of versatile multispecific antibodies with enhanced antigen-binding capacity, Fc-independent agonist activity and intermediate half-life. Trimerbody is the first and only format that complies with all the hallmarks of the Next Generation Immunostimulatory antibodies.

Our lead compound, LEAD-452, is a highly effective conditional 4-1BB x EGFR agonist bispecific Fc-less antibody which is ready to enter the clinic. 

• Multigram per litter yields (CHO cells) by standard and fully operational procedures. 
• GLP-like non-human primate (single and repeat dose) safety and pharmacokinetics studies exhibit appropriate PK and complete absence of adverse events. 
• Superior to competitors. LEAD-452 exhibits greater therapeutic window, overcoming the poor anti-tumor activity exhibited by competitors 1:1 and/or 2:2 configurations (i.e. BiTE and silenced IgGs). 

We are seeking a collaboration / licensing / co-development agreement to complete clinical manufacturing and a phase I / first-in-human basket study in advanced cancer patients including lung, colon, breast and head and neck.

Executive summary:

With regards to product differentiation, the main limitation of current immunostimulatory mAb agonists is that they lack control over the stimulation of the immune system causing serious adverse events (AEs) (infiltration and inflammatory organ failure, liver inflammation, transaminitis, thrombocytopenia and leukopenia). To solve these, strategies are being developed aimed at limiting the co-stimulation of 4-1BB to the tumor microenvironment and avoiding unwanted interactions with the numerous types of FcγRs. These approaches are mainly based on bispecific agonist antibodies (BsAb) against 4-1BB as well as tumor-associated antigens, designed with silenced effector Fc regions by specific mutations to reduce binding to FcɣRs. However, (1) total silencing of Fc is complex due to residual binding to the multiple existing FcɣRs classes, (2) immunogenicity of mutated Fc; and (3) long circulating half-life (10 to 14 days), which for an agonist antibody could be excessive and cause AEs. In fact, most silenced 4-1BB antibodies have shown clinical toxicity or modest activity. Along these lines, four clinical trials have been published so far that point in this direction.

The multiple competitive advantages of LEAD-452: The hit-and-run concept.

1. LEAD-452 allows the formation of clustered 4-1BB signaling complexes in the complete absence of the involvement of FcγRs on neighboring inflammatory cells (the problem). LEAD-452 has no Fc, thus guarantees a completely FcγRs-independent 4-1BB activation.
2. Trimeric structure: Trimerbody is the only known 3 + 3 configuration with agonist activity similar to that induced by the natural ligand of 4-1BB (4-1BBL). Compared to BsAbs with 1+1 or 2 + 2 stoichiometries (see appendix), LEAD-452 provides superior preclinical therapeutic window against a wide range of human tumors in humanized immunoavatarized mice, as well as synergy with immune check point blockers (ICBs).
3. The half-life of IgG-based molecules (silenced or not) is 10 to 14 days, which might be appropriate for antagonists mAbs (ICBs) but excessive for agonist signals. On the other hand, the half-life of configurations based on BiTE-type antibody fragments are less than 1 hour, i.e. too short, leading to early clearance and poor efficacy. In the case of half-life extension approaches (i.e., albumin conjugation), monovalent binding to 4-1BB is still clearly a disadvantage. In contrast, the half-life of LEAD-452 is around 66.8 hours, which is considered intermediate and appropriate for agonist costimulatory signals.

This conveys the "hit and run" concept that we consider crucial for 4-1BB agonists where an intermediate half-life together with the total absence of interaction with FcγRs are transcendental factors to induce an effective action and, most importantly, a safe antitumor response. 

On its way to the market, we have designed a Phase 1 study (basket type) in which cancer patients with different membrane EGFR expression profiles will be treated with increasing doses along with an extension arm in combination with the anti-PD1, pembrolizumab. In addition, to increase the response rate, we are conducting a project on the classification and underlying mechanisms that define the different tumor immune phenotypes by identifying molecular and immune biomarkers of response in EGFR-dependent cancers to guide the clinical development criteria of LEAD-452.