OrbiMed Backs Early: Yale-Spinout Gennao Bio, an AOC Biotech with Over $40M Raised, Files IPO Prospectus

In recent years, the oligonucleotide therapeutics industry has made significant progress in targeting hepatocytes and hepatic tissues. To date, 15 drugs have been approved, marking this class as the third wave of innovative medicines following small molecules and antibody-based therapies. However, due to limitations in delivery technologies and the endosomal trap, currently marketed oligonucleotide drugs are restricted to liver targets and continue to face challenges related to dose, concentration, and time dependence.

Meanwhile, antibody-based therapeutics have experienced explosive growth, with their share of the disease treatment market steadily increasing. Antibodies exhibit high-specificity affinity for tumor cell antigens, making them ideal carriers for targeted drug delivery to tumor sites. However, the antitumor efficacy of existing antibody drugs used as monotherapy is limited, and most patients who initially respond to antibody therapy tend to develop drug resistance over time.

Consequently, combination strategies involving the conjugation of antibody drugs with other therapeutic agents to create novel modalities are increasingly prevalent. New delivery approaches, such as antibody-oligonucleotide conjugates (AOCs), have garnered significant attention and emerged as an effective development strategy for tissue-specific delivery targeting organs beyond the liver. Recently, Bristol Myers Squibb (BMS) entered into a collaboration with Avidity Biosciences valued at up to $2.2 billion, aiming to leverage its AOC technology platform to develop up to five innovative therapies.

Antibody-Oligonucleotide Conjugates (AOCs) leverage the precision of oligonucleotide therapeutics and the specificity of macromolecular drugs such as antibodies, thereby addressing the targeting challenges of oligonucleotides. This enables oligonucleotide drugs to enter cells and target mRNA. Furthermore, by utilizing the stable structure of antibody drugs, AOCs enhance the stability of oligonucleotides, ultimately promoting their safe, effective, and selective application in disease treatment.

The structure of Antibody-Oligonucleotide Conjugates (AOCs) is similar to that of Antibody-Drug Conjugates (ADCs), primarily consisting of three components: a carrier that mediates tissue targeting, a linker, and small nucleic acids serving as the payload. AOCs effectively combine antibodies with small nucleic acids to achieve targeted therapy, thereby reducing the required drug dosage for disease treatment while addressing the challenges of delivering small nucleic acid drugs to previously undruggable targets. Compared with conventional small nucleic acid therapies, AOCs exhibit superior pharmacokinetic properties and more specific biodistribution.

Founded in 2020, Gennao Bio (hereinafter referred to as “Gennao”) is an innovative company strategically positioned in the field of antibody-oligonucleotide conjugates (AOCs), dedicated to developing targeted nucleic acid therapies using its proprietary non-viral gene monoclonal antibody (GMAB) platform technology. The company’s founders include Peter Glazer, M.D., from Yale University, Elias Quijano, Bruce Turner, and Dr. Stephen Squinto, CIO of J.P. Morgan Life Sciences Venture Capital Group.

In 2021, Gennao announced the completion of a $40 million Series A financing round. The round was co-led by OrbiMed and Logos Capital, with participation from Surveyor Capital. The proceeds will be used to support the development of its GMAB platform technology and the development of targeted nucleic acid therapeutic candidates for the treatment of tumors and rare monogenic skeletal muscle diseases.

Furthermore, CureDuchenne, a nonprofit organization dedicated to finding and funding treatments for Duchenne muscular dystrophy (DMD), announced a $1 million investment in Gennao. This investment is also part of Gennao’s Series A financing round, aimed at facilitating the application of its GMAB platform technology to research on Duchenne muscular dystrophy and other rare muscle diseases.

Compared with the relatively mature toxin delivery technology, antibody-nucleic acid conjugate technology is more complex. However, to achieve clinical application, it is essential to effectively deliver nucleic acid drugs into cells. Currently, there are several challenges that must be overcome:

1. Specificity and Stability: Ensure efficient binding of antibodies to nucleic acids while maintaining their specificity and stability, which requires designing appropriate conjugation strategies to prevent non-specific binding or nucleic acid degradation.

2. Delivery Efficiency: Ensure high efficiency of intracellular delivery of the antibody-nucleic acid conjugate to achieve selective delivery at therapeutic levels.

3. Immunogenicity: Avoid excessive immunogenicity of antibody-nucleic acid complexes to prevent triggering immune responses in patients.

4. Intracellular Release: Ensuring the effective release of nucleic acids from the complex within cells to achieve their biological activity.

In light of these challenges, numerous studies are developing drug delivery systems for the effective delivery of nucleic acids.

Currently, Gennao’s GMAB technology platform can effectively address these challenges. GMAB is an adaptable technology platform that utilizes cell-penetrating antibodies exclusively licensed from Yale University, enabling non-covalent binding with various nucleic acid payloads and their delivery into selected cells at therapeutic levels.

The GMAB technology platform offers multiple advantages over traditional gene delivery systems, including efficient binding and delivery of diverse payloads (such as single-stranded/double-stranded RNA, mRNA, synthetic RNA, DNA, RNAi, and ASOs), release in both the cytoplasm and nucleus, mature antibody manufacturing processes, and support for repeated dosing. Furthermore, GMAB enables targeted delivery of complexes to the nucleoside transporter ENT2, minimizing off-target effects and enhancing the intracellular bioavailability of the payloads.

In April 2022, Gennao announced the preclinical study results of its GMAB platform in various solid tumor models at the American Association for Cancer Research (AACR) Annual Meeting. Co-founder Elias Quijano presented and discussed these findings in an oral presentation titled “Targeting Therapeutic RNA Systems to Treat Cancer via Novel Cell-Penetrating and Nucleic Acid-Binding Monoclonal Antibodies.”

Preclinical study results indicate that GMAB can act as a potent activator of the RIG-I immune signaling pathway3p-hpRNAForming non-covalent complexes, they were systematically targeted and delivered to solid tumors, including orthotopic mouse models of human pancreatic cancer (KPC) and medulloblastoma (DAOY). GMAB can be highly specifically delivered into tumors by targeting ENT2 (a nucleoside transporter overexpressed in many tumors), independent of intracellular pathways. In vitro studies of GMAB/3p-hpRNA demonstrated that delivering RIG-I agonists to tumor cells triggers an immunostimulatory type I interferon response and directly leads to tumor cell death.

In the KPC pancreatic cancer model, multi-dose GMAB/3p-hpRNA administration conferred a significant survival benefit, partly attributable to a sustained increase in tumor-infiltrating lymphocytes (including CD45+, CD8+, CD4+, and CD19+ cells). Compared with the control group, GMAB/3p-hpRNA treatment also demonstrated a statistically significant increase in tumor cell necrosis. Previous studies involving single-dose GMAB/3p-hpRNA administration in an orthotopic medulloblastoma model have shown that it can penetrate the central nervous system, reduce intracranial tumor burden by 50%, and prevent spinal metastasis.

Stephen Squinto, CEO and Chairman of the Board of Gennao, stated, “The GMAB platform holds broad therapeutic potential and diverse applications in treating cancers with significant unmet medical needs. We plan to advance the Investigational New Drug (IND) enabling studies for the humanized version of GMAB/3p-hpRNA, GMAB-7001, in the second half of 2022, and will continue to evaluate other oncology pipeline candidates.” Currently, Gennao has not disclosed any information regarding its new drug development programs.

Nowadays, through chemical modifications, small nucleic acid drugs have achieved high stability. With delivery systems such as liposomes and conjugation technologies like GalNAc, efficient liver-targeted delivery has been realized. However, extrahepatic targeted delivery remains a challenging problem yet to be solved.

Currently, numerous overseas companies are focusing on the development of non-liver-targeted delivery technologies. In addition to Gennao, global enterprises with AOC candidates in development include Avidity Biosciences, Dyne Therapeutics, Tallac Therapeutics, and Denali Therapeutics.

November 2021,Avidity Biosciences, a pioneer in antibody-oligonucleotide conjugates (AOCs), has administered the first dose in its Phase I clinical trial of AOC1001, marking the entry of the world’s first AOC drug into clinical trials.Dyne Therapeutics’ AOC drug also initiated patient enrollment in clinical trials in September 2022. Tallac Therapeutics plans to advance TAC-001 into clinical development. Denali Therapeutics’ DNL310 is currently in Phase I/II clinical trials. The AOC programs developed by these companies target indications spanning muscular diseases, central nervous system disorders, and cancer.

This November, BMS announced a spending ofOver $2.2 billion, introducing Avidity’s AOC technology to develop multiple innovative drugs targeting cardiovascular indications. Previously, Avidity collaborated with BMS’s MyoKardia on research to demonstrate the potential utility of AOCs in cardiac tissue. This year’s strategic partnership marks BMS’s renewed commitment to the cardiovascular sector, while also expanding the scope of Avidity’s AOC platform. Avidity will continue to advance its internal R&D programs focused on rare cardiac indications.

There are relatively few companies in China focusing on the AOC sector, mainly including Zhongmei Ruikang, Youjia Bio, Jiajin Bio, and Hongliang Bio.Gennao Bio, Inc. is among the first companies in China to engage in the research and development of small nucleic acid conjugate drugs,Focusing on extrahepatic delivery of small nucleic acids via conjugation, the company will prioritize rare diseases, oncology, and central nervous system disorders to drive innovation in its platform technology. Its core pipeline candidate, CGB1001, is indicated for myotonic dystrophy type 1 (DM1). CGB1001 has yielded positive data in preclinical animal studies, is scheduled to advance to the Preclinical Candidate (PCC) stage in 2023, and will rapidly initiate Investigational New Drug (IND) application filings.

Zhongmei Ruikang possesses internationally leading SCAD (Smart Chemically Assisted Delivery) technology, which enables efficient delivery to extrahepatic tissues (such as the central nervous system, heart, muscle, lungs, and eyes). Youjia Bio has developed nanobody-nucleic acid conjugate (nAOC) technology. Hongliang Bio has developed GaINA/siRNA, SNP/RNA, and Affibody/RNA (AOC) delivery technologies.

Currently, the overall R&D of Antibody-Oligonucleotide Conjugate (AOC) drugs remains in its early stages, with multiple technical hurdles yet to be overcome; in particular, the development of targeted delivery systems and optimization of therapeutic efficacy need to be accelerated. It is believed that as these challenges are addressed and indications expand, the AOC drug sector will witness a true surge in growth.