Aktis Oncology - The Miniprotein Radioconjugate Platform (Pt 1) $akts

Protein-Protein Interactions, Peptides vs Antibodies, Pluvicto.

My last note explored different nucleic acid approaches for treating muscular diseases. This included discussion of therapeutic delivery vehicles, whether that be an antibody (Avidity), antibody fragment (Dyne), linear peptide (PepGen), cyclic peptide (Entrada), or peptide ligand (Arrowhead). This week I’m also writing about delivery vehicles, but applied to a different problem: solid tumor cancers.

The recent story of cancer treatment has really been around improving the ability to precisely target cancerous cells over healthy cells. This isn’t what traditional chemotherapy does, as explained by Endocyte pre its acquisition by Novartis:¹

“Traditional cytotoxic cancer chemotherapies kill rapidly dividing cancer and normal cells in an indiscriminate manner, leading to significant toxicity in patients. The need for patients to recover from this toxicity can limit the ability to deliver effectively-dosed cancer therapy. In addition, cancer therapies for a given tumor type are generally selected based on observations of efficacy and toxicity in that patient population and not, in most cases, based on an understanding of the differences between tumors on a molecular level.”²

Antibody-drug conjugates (ADCs) try to improve upon both these limitations. Take Padcev, used to treat a subset of patients with cancers of the bladder or urinary tract. The monoclonal antibody portion of the drug binds to Nectin-4, a surface protein overexpressed in a variety of cancers. Once this binding occurs the ADC is then brought within the cell (via receptor mediated endocytosis), and the cytotoxic payload MMAE (monomethyl auristatin E) gets to work preventing further cancerous cell division. Unlike chemotherapy, MMAE is too toxic to be delivered to patients ‘naked.’ Its conjugation with an antibody enables it to very precisely target the cancerous cells, rather than just any cells that are dividing quickly.

Therapeutic radiopharmaceuticals are similar in principle to ADCs. They’re specifically targeted, and contain a payload that in most cases couldn’t be delivered to patients absent some type of conjugate.³ In the case of radiopharmaceuticals, as the name suggests, a radionuclide is used to kill the cancerous cells. There are two FDA approved targeted therapeutic radiopharmaceuticals that have generated significant investor/pharma excitement: Lutathera and Pluvicto.⁴ Both are owned by Novartis, both treat types of cancer, both use a peptide or peptidomimetic-conjugate, and both are expected to have peak annual sales exceeding a billion (exceeding 5 billion in the case of Pluvicto).

Aktis Oncology, which went public earlier this month (with an 100mm anchor investment from Eli Lilly), is another company playing in the targeted radiopharmaceutical space. The S1 spends a lot of time emphasizing the benefits of its miniprotein radioconjugate platform, as well as describing the limitations of using either peptides or antibodies to direct radionuclide payloads.

In an ideal world, antibodies probably wouldn’t be the conjugate of choice for guiding cancer treatment. They’re expensive/time-consuming to produce (which affects production of the final product and the ease of validating initial targets during drug discovery), challenging to modify during the drug development process, can cause an immune response in patients, and exhibit poor tissue penetration in solid tumors.

Compared to antibodies, peptides are cheaper/faster to produce, easier to modify, don’t cause the same immune response, and exhibit much better solid tumor tissue penetration (all else equal, a smaller amino acid chain is going to have an easier time penetrating tissue than something much larger). Unfortunately, in the context of treating solid-tumor cancers peptides currently come with some downsides.

Peptides (and many small molecules!) work well when there’s a clearly defined binding site to interact with. This point is well demonstrated by Pluvicto and Lutathera. Pluvicto targets the prostate-specific membrane antigen (PSMA), a protein overexpressed in those with prostate cancer. PSMA is also an enzyme, so as expected has a well defined active site. Lutathera targets the somatostatin receptor 2 (SSTR2), which is both overexpressed in certain gastroenteropancreatic neuroendocrine tumors and exists as a receptor for an endogenous peptide.

Regrettably, there are plenty of proteins overexpressed in cancer that don’t have such perfectly defined binding sites. It is here that peptides (and small molecules!) struggle. In these cases, affecting cancer growth requires affecting protein-protein interactions (PPIs).⁵ Protein-protein interactions are quite different from how an enzyme/substrate or peptide/receptor work together. In high school biology, one is taught to think about an enzyme and its substrate fitting together like a lock and key. Such an analogy doesn’t work when thinking about PPIs. Crudely, one can think of the difference in indoor climbing/bouldering terms. At the beginner level, holds can be so thick and made for hands that a climber can keep himself on the climbing wall with only one point of contact. Things change, however, once one moves onto more difficult routes. At that stage, the holds become so small/awkward to hold onto that multiple points of contact (and keeping your body tight into the wall rather than hanging off leisurely) and required to succeed.⁶ So it goes for enzyme/substrates vs PPIs. The enzyme active site is designed to make it easy for the substrate to hang on. PPIs, however, are like the harder climbing route. The surfaces of these proteins are largely flat, and held together primarily by weak hydrophobic interactions, requiring many more points of protein-protein contact.

This presents a few challenges for the peptide approach:

1) When not bound to the target protein, peptides exist in a linear, flexible state. Binding to the protein requires that the peptide take on a well-defined 3D structure, but that change from less-ordered to more-ordered is not entropically favorable! Consequently, peptides tend to have quite weak affinity for these protein targets. When there’s a well defined binding pocket for a peptide this entropic penalty can be overcome due to the strong bonds formed, but that doesn’t occur with a mostly flat surface.

2) Because peptides typically exist in that flexible state, this means they can take on different 3D structures to bind with proteins other than the one with therapeutic potential. This increases the risk of off target affects. Put differently, peptides often have poor selectivity.

3) Because peptides exist in that linear state they have a limited surface area. This limits the number of hydrophobic interactions that can occur.

A peptide that can impact PPIs would ideally have a larger surface area and already be in the conformation required to bind to the protein of interest. The larger surface area allows for greater hydrophobic interactions, and the pre-set conformation means there’s not the same entropic penalty for the peptide binding to the protein.⁷

It is here where Aktis’ miniprotein platform comes in. The company’s miniproteins are 40-70 amino acids in length, and so while longer than typical peptides are far smaller than typical antibodies. Critically, this slightly longer length means these miniproteins do have a 3D conformation, and so have a larger surface area, better binding affinity, and less potential for off-target interactions. In theory, miniproteins gives Aktis all the aforementioned benefits of peptides, but also overcome their principal limitations. This is why Aktis is developing therapies for Nectin-4 and B7-H3 expressing tumors.⁸ Historically, these proteins have been a better fit to target with antibodies rather than peptides, and so are an ideal proving ground for the company’s thesis. In its S1 Aktis claimed to have “reproducibly generated sub-nanomolar affinity miniprotein binders to specific tumor targets.”⁹ This would be a big deal, putting its miniprotein binders on par with Lutathera, and indicating the company has overcome binding affinity issues typically present with peptides and PPIs .

From an investor standpoint, it’s important that the length of these miniproteins mean they’re considered biologics, not small molecules.¹⁰ In other words, the patent protection for these therapeutics would be twelve years rather than five. This isn’t the case for Lutathera or Pluvicto, which is why Lantheus Holdings is trying to bring a Lutathera generic to market. This should mean Aktis has an advantage raising additional capital when compared to any peptide-conjugate competitors - the net present value calculation is quite different when your product is protected for an extra seven years!

Disclaimer: The information in this post is not intended to be and does not constitute investment or financial advice. You should not make any decision based on the information presented without conducting independent due diligence.

1. I picked Endocyte because Novartis bought the company for its radiopharmaceutical pipeline, which included Pluvicto.

2. Pg 5, 2017 Endocyte Annual Report.

3. A conjugate isn’t needed in the case of Xofigo, which was approved by the FDA in 2013 for treatment of prostate cancer that’s reached the bone. Xofigo is unique in that the radionuclide it uses looks very similar to calcium, and so is primarily taken up the bone/doesn’t pose much risk of off-target effects.

4. In this piece I’m ignoring radiopharmaceuticals used for diagnostic purposes, as well as Xofigo.

5. You’ll often see the KRAS gene mentioned in this context. KRAS mutations are associated with driving many different cancers, but for decades the protein was considered undruggable due to its smooth surface and lack of an obvious binding pocket.

6. This analogy really only works in the case of beginner climbers, rather than advanced ones with crazy grip strength!

7. These are also the characteristics Bicycle Therapeutics is aiming to give its bicyclic peptides.

8. Its Nectin-4 targeting radiotherapeutic is in Phase 1b trials, with preliminary results from the pt 1 dose escalation portion of the trial expected in Q12027. Aktis plans to file an IND for its B7-H3 targeting radiotherapeutic in the second half of 2026.

9. Pg 4, Aktis S1.

10. Conveniently, the FDA considers a biologic to be an amino acid polymer greater than 40 amino acids in length.