ELI-003: Our Product Candidate for ALK-driven Cancers
In addition to our KRAS program and our AMP adjuvant initiative, we are evaluating our ALK program as a potential internal development candidate. Characteristics of ALK-driven disease and the likely costs of a clinical development initiative may support its further consideration as the target of an independent development candidate.
ALK is the gene that codes for the signaling protein, anaplastic lymphoma kinase. Translocations involving the ALK gene are responsible for approximately 5% of all NSCLC cases. Like KRAS, ALK is a primary driver mutation, with tumor selective and consistent expression maintained in all tumor cells throughout disease progression. While the use of tyrosine kinase inhibitors, or TKIs, to treat ALK-driven cancers has proven highly effective, the therapeutic benefit of TKIs is of limited duration, as resistance is almost universally developed, requiring an alternative therapeutic strategy. CPIs alone have not been shown to be effective against ALK-driven cancers.
Preliminary investigations suggest that vaccination against ALK using an AMP-modified CpG adjuvant result in therapeutic immunity. Studies involving a mouse model showed that use of an AMP vaccine increased survival. Moreover, the use of ELI-003 may act in a complementary and possibly synergistic manner with TKI therapy and may enable increased CPI efficacy.
ELI-007: Our Product Candidate for BRAF-driven Cancers
ELI-007 is a multivalent lymph node targeted AMP-peptide vaccine directed at BRAF V600E mutations. BRAF V600E mutations are present in 40% of melanoma, 10% of colon cancer and 2% of lung cancer. While available small molecule inhibitors generate initial responses in BRAF V600E-mutated melanoma, these responses are not sustained because of resistance due to alternative growth signaling pathways, and few initial responses occur in BRAF-mutated colon cancer. Previous research has shown that T cells can respond to the driver mutation V600E in BRAF and that transfer of tumor-infiltrating lymphocytes that recognize mutated BRAF resulted in durable complete response in a case study. The protein expression of BRAF V600E is maintained at high levels in these tumors suggesting that they would be susceptible to T cells specific for the mutated BRAF.
ELI-008: Our Product Candidate for TP53-driven Cancers
ELI-008 is a multivalent lymph node targeted AMP-peptide vaccine directed at p53 hotspot mutations. Like KRAS, mutations in p53 are found in a large number and wide variety of cancers, accounting for approximately 60% of patients with solid tumors. ELI-008 is being developed to target hotspot mutations in p53 in solid tumors including colorectal cancer, melanoma and non-small cell lung cancer (NSCLC). An AMP-peptide vaccine targeting p53 hotspot mutations may be able to potently expand and mature tumor-specific T cells through enhanced delivery and immune stimulation in draining lymph nodes to generate tumor-specific immunity capable of eliminating tumor tissue.
ELI-011: Our CD19 CAR-T AMPlifier Program
Based on the additive effects observed in mouse models combining AMPlifiers and CAR-T therapies, an AMP-based immunotherapy administered in conjunction with a CAR-T therapy may generate efficacy improvements. We have entered into a collaboration with the Moffitt Cancer Center to evaluate the combination of our CD19 CAR-T AMPlifier, which we refer to as ELI-011, together with CD19-targeted CAR-T therapy, in mouse models of B cell lymphoma. Positive results in these preclinical assessments may support the advancement of the program into clinical trials.
Despite high initial response rates with marketed CD19-specific CAR-T therapies, cancer progressed in more than 50% of patients following treatment. This progression may correlate with poor expansion and persistence of the administered CAR-Ts. Our AMPlifiers have been observed to overcome this limitation in preclinical studies, as well as improve trafficking into the tumor and enhance the functional quality of generated T cells, required to stimulate increased cytokine production. These results may be indicative of the potential of an AMPlifier, in combination with engineered T cells (including marketed CD19-specific CAR-T therapies), to improve durability of response.
ELI-005: Our Product Candidate for Prevention of COVID-19
We have conducted initial assessments of the AMP platform for inducing immune responses targeting SARS-CoV-2 and it may be well suited as a vaccine using an AMP adjuvant. Coronavirus infectious disease 2019, or COVID-19, caused by the novel coronavirus SARS-CoV-2, has swept rapidly throughout the world in 2020 and 2021. In early 2020, the World Health Organization, or WHO, declared COVID-19 a public health emergency of international concern.
SARS-CoV-2 is an enveloped, single-stranded, positive-sense RNA virus belonging to the family Coronavidae and the genus ß-coronavirus. The genome of SARS-CoV-2 encodes one large Spike protein (S), which plays a pivotal role during viral attachment and entry into host cells. The S protein has been frequently considered as the major antigen target for vaccines against human coronaviruses such as SARS-CoV, and MERS-CoVbecause it contains the major epitopes targeted by neutralizing antibodies, and in more recent studies has also been considered for vaccines against SARS-CoV-2. We have developed a vaccine candidate focused on specific regions encoded by the S domain of the viral genome.
We are working to deploy our AMP platform to potentially address the COVID-19 crisis. Our AMP-CpG adjuvant has been manufactured in a separate cGMP workstream, so that it can be combined with different SARS-CoV-2 antigens. At this point in the pandemic, coverage for the currently circulating strains is important. For example, compared to the Spike RBD sequence of the initial SARS-CoV-2 strains in circulation worldwide, strain B.1.1.7, known as the United Kingdom, or UK, variant, has a single amino acid difference; strain P.1, known as the Brazilian variant, has three amino acid differences; and strain B.1.351, known as the South African variant, has three amino acid differences. The RBD is an important target for the immune response because it is the target for neutralizing antibody responses to SARS-CoV-2 and related coronaviruses including MERS and the original SARS virus. Likewise, these Spike antigens contain T cell epitopes, generating cell mediated immunity in SARS-CoV-2, MERS and SARS. The strong T cell responses generated by ELI-005 suggest that it may address these variants, since the majority of amino acid regions recognized by T cells have been conserved in the South Africa and UK strains