Delivering RNA to Target Cells in Cancer and Inflammatory Disease Indications

Altamira’s OligoPhore™ / SemaPhore™ platform is a versatile system that allows complexation of therapeutic RNAs with a proprietary peptide to form a nanoparticle formulation. This formulation allows to deliver therapeutic RNA by systemic administration to tissues affected by leaky vasculature, a hallmark of solid tumors and certain inflammatory conditions. The OligoPhore™ / SemaPhore™ technology has been extensively and successfully tested with various siRNA and mRNA sequences in over 15 disease models in mice.

We are developing our OligoPhore™ and SemaPhore™ platforms for oligonucleotide and mRNA delivery with two strategic aims: 1) to develop proprietary drug products, and 2) to leverage the platforms through collaboration with partners in well-defined additional therapeutic areas. For our proprietary development program, we are initially focusing on two flagship projects:

AM-401 for the treatment of KRAS-driven cancers
AM-411 for the treatment of rheumatoid arthritis

Development Status

AM-401: KRAS-Driven Cancers

The KRAS gene encodes the K-Ras protein which controls - like an “on / off switch” – cell growth, maturation, migration and death. Through mutations, the K-Ras proteins can be rendered persistently active, causing cancer cells to proliferate and spread in the body. Mutations of KRAS are associated with poor prognosis in several cancers, and there is a substantial body of evidence supporting the role of KRAS in the initiation and maintenance of cancer.

There are more than a dozen different KRAS mutations in human cancer, but the prevalence of each mutation is variable among different types of cancers. Mutated forms of KRAS are found in one-fifth of all human cancers, including 32% of non-small-cell lung cancers, 40% of colorectal cancers and 85–90% of pancreatic cancers (Herdeis et al., 2021). According to the American Cancer Society, almost 150,000 new cases of KRAS mutated tumors are diagnosed in the United States alone across these three tumors types each year. It has been estimated that mutations in KRAS alone account for approximately one million deaths per year worldwide (Simanshu et al., 2017).

AM-401 is an intravenously administered nanoparticle based on the OligoPhore™ platform targeting KRAS. In contrast to small molecule inhibitors, that are designed to inhibit KRAS harboring one specific mutation, Altamira’s approach, polyKRAS^mut, is polyvalent as it allows for silencing KRAS carrying any of the most abundant mutations described for this oncogene. Proof-of-concept has been obtained in well-established mouse models of pancreatic cancer; and biodistribution studies have shown specific delivery of the siRNA to the tumor tissue. Altamira plans to file an IND in 2025.

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KRAS-OligoPhore nanoparticles inhibit tumor growth in a mouse model of pancreatic cancer. Tumor volume following treatment of KPC-1 tumor bearing mice starting one week post-tumor engraftment with KRAS-OligoPhore nanoparticles or scrambled counterparts. Strand et al., 2019

AM-411: Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory condition causing joint swelling and pain which may also affect other areas, including the skin, eyes, brain, and cardiovascular system. In the US in 2014, approximately 1.3 million adults suffered from RA (Hunter et al., 2017) and according to the World Health Organization (WHO), the autoimmune disease affects globally up to 18 million people. RA affects 1 in 28 women and 1 in 59 men during their lifetime (Crowson et al., 2012).

There is no cure for RA; current treatments seek to manage RA with biologic and non-biologic immunosuppressants, corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs). While useful, drug resistance occurs in up to 50% of patients and systemic adverse reactions are frequent, including rash, hair loss, altered liver function, low blood cell counts, nausea, increased infections and neuropathy. New biologics targeting JAK/interleukins have been issued black box warnings by the FDA. The global antirheumatics market is expected to grow from $57.9 billion in 2019 to $62.9 billion in 2027 (Allied Market Research).

AM-411 is an intravenously administered nanoparticle based on the OligoPhore™ platform targeting p65, one of the main transcriptional regulators of the NF-kB pathway and a key checkpoint in RA inflammation. AM-411 has been designed to reduce local inflammation without affecting the NF-κB pathway outside the inflamed tissue and is less likely to generate resistance because it reduces synthesis of p65 rather than blocking the protein. An IND filing is planned for 2025.

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Reduction of inflammation, ankle thickness and arthritis score in response to p65-OligoPhore nanoparticles compared to scrambled siRNA nanoparticles or HBSS. Zhou et al., 2014

Overview of Key Studies

Cancer Models	Target	RNA
Pancreatic and colorectal cancer	KRAS	siRNA
Ovarian cancer	TAM: AXL	siRNA
Lung cancer	ETV-2	siRNA
Metastatic melanoma	NF-κB	siRNA
Adult T-cell Leukemia / Lymphoma (ATLL)	NF-κB	siRNA
Sarcoma	MYCT-1	siRNA
Sarcoma and breast cancer	MYCT-1	siRNA
Tumor microenvironment	ZBTB46	mRNA

Inflammatory Models	Target
Necrotizing enterocolitis	NF-κB	siRNA
Rheumatoid and osteoarthritis	NF-κB	siRNA
Artherosclerosis	JNK2	siRNA
Metabolic syndrome / obesity	ASXL2	siRNA
Aortic aneurysm	NF-κB	siRNA
Osteoarthritis	WNT16	mRNA
Atherosclerosis	P27Kip1	mRNA
Aortic aneurysm	SOD2	mRNA

Partnering

Altamira’s OligoPhore and SemaPhore platforms offer solutions for extrahepatic delivery of nucleic acid therapeutics. Advantages include protection of the therapeutic cargo from degradation and clearance, access to extrahepatic tissues and highly efficient endosomal release. Altamira is open to strategic collaborations with parties interested in:

In-licensing/collaboration on our OligoPhore/SemaPhore delivery technology for specific payloads, indications, or tissues.
In-licensing/collaboration on our siRNA therapeutic candidates AM-401 (targeting polyKRAS^mut in KRAS-driven cancers) or AM-411 (targeting NF-kB in rheumatoid arthritis).