Enzyme engineering for rare genetic diseases and cancer
Aeglea BioTherapeutics is engineering human enzymes for the treatment of both rare genetic diseases and cancer.
Amino acids (AAs) are fundamental building blocks of life, making up proteins, cycling nitrogen, providing energy and transmitting signals. Nine of the 21 AAs found in proteins are ‘essential’, meaning they must come from dietary sources. Four other AAs, including arginine and cysteine, are ‘semi-essential’, meaning there are biosynthetic pathways to produce them in humans, but a dietary source is required in some circumstances. Although adequate supplies of these AAs are clearly necessary for health, an oversupply of some AAs can, perhaps surprisingly, be devastating and even fatal.
Aeglea BioTherapeutics is a leader in the creation and development of novel human enzymes that act in the circulation to degrade specific AAs. Aeglea’s engineered proteins are designed as enzyme-replacement therapies for the treatment of rare genetic diseases, removing excess AAs that would otherwise accumulate to toxic levels. These enzymes also hold promise as therapies for certain cancers that have become dependent on AAs to fuel their growth. The depletion of key AAs in blood may selectively starve tumor cells, targeting a tumor growth pathway that otherwise can’t be blocked by antibodies or small-molecule therapeutics.
Aeglea is focused on discovering and developing treatments for abnormalities in AA metabolism for which the biology is well understood and there is a compelling unmet medical need. Rare genetic diseases are a large collection of over 700 disorders, including in AA metabolism. These rare metabolic diseases currently have limited treatment options, and no single therapy is appropriate to treat the full range of diseases. Aeglea concentrates its efforts on treatments that are amenable to a blood-based mechanism of action. According to Aeglea’s CEO, David G. Lowe, this focus offers a high probability of success in creating effective treatments that will have a substantial impact on the course of disease. Serum AA levels are an accessible and clinically meaningful pharmacodynamic measure that provides proof of mechanism and serves as a potential surrogate marker for clinical benefit. Clinical and preclinical testing of several engineered human enzymes has shown reduced AA levels in blood after treatment.
All cells require a balance of AAs for normal function, but tumor cells can become particularly dependent on specific AAs. The energetic cost of AA production is high. In some cases, tumor cells can gain a growth advantage during oncogenesis by suppressing certain biosynthetic pathways, such as synthesis of the semi-essential AA arginine. While it creates a growth advantage for the tumor, the loss of this pathway also provides Aeglea with a potential biomarker or companion-diagnostic strategy to identify arginine-dependent tumors that are vulnerable to a reduction in arginine. Two US Food and Drug Administration– approved microbial enzymes that target asparagine conceptually validate AA targeting in cancer treatment, although immunogenicity appears to be a limiting factor for this approach. Although it is generally thought that the human genome cannot provide direct product candidates enabling broader exploitation of tumor dependence on AAs, Aeglea believes that its product candidate AEB1102, an engineered human arginase enzyme, has the potential to reduce blood arginine levels and to be less immunogenic than microbe-derived enzymes.
AEB1102, Aeglea’s first product candidate to enter the clinic, has been shown to reduce blood arginine levels in clinical studies, thus providing proof of mechanism. Aeglea has an open phase 1/2 trial in the United States for patients with impaired arginine degradation caused by a mutation in the arginase 1 gene (ARG1) (Fig. 1). ARG1 deficiency is a devastating, life-threatening urea-cycle disorder that presents in early childhood. Affected children develop neurologic symptoms, such as spasticity, seizures and neurocognitive deficits that may ultimately lead to severe intellectual disability. To date, no therapy has been approved that addresses the fundamental defect underlying the disease. To Aeglea’s knowledge, AEB1102 is the first attempt to create a potential enzyme-replacement therapy for ARG1 deficiency. The hope is that it may dramatically alter patients’ lives if treatment is begun early in life, thereby delaying or even preventing progressive neurological and neurocognitive impairment.
Figure 1: Aeglea’s product pipeline.
AEB1102 is also currently in phase 1 trials in cancer patients with advanced solid tumors and with hematological malignancies. Biomarkers of tumor dependence on arginine have shown value as predictors of sensitivity to arginine depletion—for example, in patient-derived xenograft models with a direct cell-killing effect—and will help guide the selection of future cancer indications to pursue in later clinical trials with AEB1102.
This work has focused Aeglea’s attention on a select number of tumors predicted to be arginine-dependent, such as small-cell lung cancer, cutaneous melanoma, uveal melanoma, Merkel cell carcinoma, acute myeloid leukemia and myelodysplastic syndromes. Furthermore, contrary to expectation, arginine depletion is not broadly immunosuppressive. In preclinical studies, Aeglea has found additive or synergistic activity of arginine depletion with AEB1102 in combination with immune-checkpoint inhibitors, opening the possibility of combination trials.
In addition to the ongoing trials with AEB1102, Aeglea has a robust pipeline of engineered human enzymes that target other key AAs (Fig. 1). These product candidates degrade cysteine and its oxidized form, cystine, to target tumor dependence on glutathione for protection against oxidative stress, as well as methionine, an essential AA for which some cancers have an increased appetite. A third enzyme, AEB4104, degrades homocystine, which accumulates in people with the rare genetic disease classical homocystinuria as a result of a deficiency of the enzyme cystathionine β-synthase. Aeglea is committed to creating value by pursuing multiple clinical pathways in parallel, each focused on diseases with the potential to be markedly affected by a single enzyme.