Oligo therapeutics vs ADCs. How do they stack up?
Biologics, such as antibody therapeutics have revolutionised our approach to the treatment of disease. Therapeutic antibodies have become the predominant class of drugs in the development pipeline and the best-selling drugs in the pharmaceutical market, revealing new treatments for cancer, autoimmune, metabolic and infectious diseases.
New modalities for new therapeutic solutions/ After antibody therapeutics, what’s next?
With antibody therapeutics now considered an established technology, newer modalities being pursued through the clinic include antibody-drug conjugates (ADCs) and oligo therapeutics. These new therapies offer hope for novel treatments, to improve the therapeutic index of current medicines through improved targeting to specific tissues, and to be able to target previously untreatable diseases that have failed with standard antibody therapies.
A recent poll across social media channels showed the perceived success of these two modalities, with oligo therapeutics being perceived as more successful than ADCs, despite the accepted success of therapeutic antibodies as the basis for these molecules.
Of the next-gen technologies progressing through the clinic, which do you perceive as the most successful?
Here we look at these new molecules and examine their progression and successes.
ADCs hitting the target
The concept of an ADC is simple; an antibody molecule is attached to a toxic chemotherapeutic payload via a biodegradable linker for targeted delivery to the tumour. This increases the effective dose at the site of action and decreases off-target effects. The primary goal of ADCs is to improve the therapeutic index of the delivery cargo by restricting their systemic delivery to cells that express the target antigen of interest.
After Pfizer launched the first ADC, Mylotarg, in 2000, the field exploded with interest. But, despite the promise of this new ‘magic bullet’ for cancer, it took over 11 years for the next ADC to reach approval. A phase IV clinical trial raised toxicity concerns, which resulted in Mylotarg being withdrawn from the market in 2010. However, it was reintroduced in 2017 after the FDA cleared it at a lower dose for a subset of leukemia patients.
ADCs are often assumed to be the next step for the field of antibody therapeutics. They are beginning to show clear promise in diseases that have been difficult to treat with other molecules, such as solid tumours.
While the concept of an ADC may be simple, developing ADCs is proving far more challenging. More than 50 companies are currently working on ADC development; over 100 ADCs are in active clinical development and over 200 at the preclinical stage. Despite this considerable promise, only 12 ADCs have so far received FDA approval.
ADCs approved for market
To date a total of 12 ADCs have been approved by the FDA, all of which have been approved for the treatment of various cancers.
|Pfizer/Wyeth||Gemtuzumab ozogamicin||CD33||Relapsed acute myelogenous leukemia (AML)||2017, 2000|
|Seattle Genetics, Millenium/Takeda||Brentuximab vedotin||CD30||Relapsed HL and relapsed sALCL||2011|
|Genetech, Roche||Trastuzumab emtansine||HER2||HER2+ metastatic breast cancer following treatment with trastuzumab & a maytansinoid||2013|
|Pfizer/Wyeth||Inotuzumab ozogamicin||CD22||Relapsed or refractory CD22+ B-cell precursor acute lymphoblastic leukemia||2017|
|AstraZeneca||Moxetumomab pasudotox||CD22||Adults with relapsed or refractory hairy cell leukemia||2018|
|Genentech, Roche||Polatuzumab vedotin-piiq||CD79||Relapsed or refractory diffuse large B-cell lymphoma||2019|
|Astellas/Seattle Genetics||Enfortumab vedotin||Nectin-4||Adults with locally advanced or metastatic urothelial cancer following treatment with a PD-1/PD-L1 inhibitor and a Pt-containing therapy||2019|
|AstraZeneca/Daiichi Sankyo||Trastuzumab deruxtecan||HER2||Adults with unresctable or metastatic HER2+ breast cancer following 2+ prior anti-HER2 based regimens||2019|
|Immunomedics||Sacituzumab govitecan||Trop-2||Adults with metastatic triple -ve breast cancer following at least 2 prior therapies for patients with relapsed or refractory metastatic cancer||2020|
|GlaxoSmithKline||Belantamab mafodotin-blmf||BCMA||Adults with relapsed or refractory multiple myeloma||2020|
|ADC Therapeutics||Loncastuximab tesirine-lpyl||CD19||Large B-cell lymphoma||2021|
|Seagen Inc||Tisotumab vedotin-tftv||Tissue factor||Recurrent or metastatic cervical cancer||2021|
All of the approved ADCs use small molecule drugs as cargo to reduce the toxicity of these molecules to non-cancerous tissues. Nonetheless, newer ADCs in development include antibodies conjugated to alternative molecules, such as oligos, to integrate these two technologies and improve the delivery of the oligo therapy to the intended tissue or cell type using target-specific antibodies.
Oligo therapies are maturing as a modality
Oligo therapeutics include a broader category of therapies than ADCs, with antisense oligonucleotides (ASOs), siRNA, and aptamers all representing examples of oligo therapies.
Gene silencing, through ASOs and siRNA, acts to reduce the expression of specific disease-associated genes. These high-precision oligo therapies are typically very potent, allowing for smaller doses than alternative biologics. They interact with their target molecules via complementary Watson-Crick base pairing, so interrogating the putative sequence is relatively straightforward. Highly specific lead compounds can often be rationally designed based on the knowledge of the primary sequence of a target gene. These oligo therapies can be easily applied to precision medicine approaches, as they can be targeted to any gene with minimal or predictable off-target effects. However, despite these advantages, achieving efficient delivery of ASO and siRNA oligo therapeutics, particularly to extrahepatic tissues, remains a major translational limitation.
Aptamers are also oligonucleotide therapeutics that can be used directly as agonists or antagonists or as an antibody alternative for the targeted delivery of specific cargo to the therapeutic site-of-action. Aptamers are selected from libraries based on their ability to fold into 3D shapes and specifically interact with a range of targets types from proteins to small molecules and ions, in the same way as antibodies.
The first approved oligo therapeutic was a 21 nucleotide ASO, fomivirsen, in 1998, which worked by blocking translation. It was approved for the treatment of cytomegalovirus (CMV) retinitis — a severe infection of the retina that can rapidly lead to blindness — in carriers of human immunodeficiency virus (HIV) that exhibited acquired immune deficiency syndrome (AIDS). Though fomivirsen was later withdrawn from the market, in 2001 due to safety issues, its success acted as a proof-of-concept paving the way for the wave of oligo therapeutics that followed.
Although most oligo therapeutics to date have focused on gene silencing, other strategies are being pursued, including splice modulation and gene activation. This could expand the potential target range of these treatments beyond that which is normally accessible to standard drug modalities.
There are currently well over 200 clinical trials ongoing for different formats of oligonucleotide therpaeutics, including ASOs, siRNA, miRNA, aptamers and DNAzymes, and 15 approved oligo therapeutics.
Oligo therapeutics reaching their stride
Among the 15 oligo therapeutics approved to date, there has been a focus on hepatic delivery with few extrahepatic successes, due to the difficult nature of targeting these tissues and organs. As a problem commonly cited with ASO and siRNA oligo therapeutics is targeted delivery of these drugs, many are now exploring the potential to use aptamer delivery vehicles to increase the delivery of the therapeutic to the target tissue or cell type.
Aptamer Group is currently working with a number of partners to develop our next-generation aptamers, Optimers, as delivery vehicles for small molecule drugs and oligo therapeutics to target a range of tissues, including haematological cancers and the kidney cortex.
|Ionis Pharmaceuticals, Novartis||Fomivirsen||CMV protein IE2||Cytomegalovirus retinitis||ASO||1998|
|OSI Pharmaceuticals||Pegatanib||Heparin binding domain of VEGF-165||Neovascular age-related macular degeneration||Aptamer||2004|
|Kastle Therapeutics, Ionis Pharmaceuticals, Genzyme||Mipomersen||Apoliporprotein B100||Homozygous familial hypercholesterolemia||ASO||2013|
|Sarepta Therapeutics||Eteplirsen||Exon 51 of DMD||Duchenne muscular dystrophy||ASO||2016|
|Ionis Pharmaceuticals, Biogen||Nusinersen||Exon 7 of SMN2||Spinal muscular atrophy||ASO||2016|
|Jazz Pharmaceuticals||Defibrotide||Adenosine A1/A2 receptor||Veno-occlusive disease in liver||Mixture of oligos derived from porcine mucosal DNA||2016|
|Akcea Therapeutics||Inotersen||Transthyretin||Polyneuropathy caused by hereditary transthyretin-mediated (hATTR) amyloidosis||ASO||2018|
|Boston Children’s Hospital||Milasen||CLN7||Mila Makovec’s CLN7 gene associated with Batten disease||ASO||2018|
|Alnylam||Patisiran||Transthyretin||Polyneuropathy caused by hATTR amyloidosis||siRNA||2018|
|Sarepta Therapeutics||Golodirsen||Exon 53 of DMD||Duchenne muscular dystrophy||ASO||2019|
|Alnylam||Givosiran||5-aminolevulinic acid synthase||Acute hepatic porphyria||siRNA||2019|
|Akcea Therapeutics||Volanesorsen||Apolipoprotein C3||Familial chylomicronemmia syndrome||ASO||2019*|
|NS Pharma||Viltolarsen||Exon 53 of DMD||Duchenne muscular dystrophy||ASO||2020|
|Novartis||Inclisiran||PCSK9||Primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia||siRNA||2020*|
|Sarepta Therapeutics||Casimersen||Exon 45 of DMD||Duchenne muscular dystrophy||ASO||2021|
|*Approved for use by the EMA, but not yet approved by FDA|
This table does include four different classes of oligo therapeutics; ASOs, siRNA, aptamers and a mixture of single-stranded oligos derived from porcine DNA. The breakdown of the various modalities can be seen in the following pie chart.
How do ADCs and oligo therapeutics compare?
When considered alone, the maximum number of a single modality is the approval of ten ASOs, two less approved drugs than the number of ADCs.
Compared to antibody therapies, for which the FDA approved the 100th monoclonal antibody therapeutic earlier this year, both ADCs and oligo therapeutics are next-generation drugs, which are establishing themselves as significant modalities. We are now refining our understanding of how to best engineer both ADCs and oligo therapeutics for improved efficacy and novel disease targeting.
At Aptamer Group, we are working with key partners across the industry to enable their therapeutic pipelines with the use of our next-generation aptamers as both direct APIs and as delivery vehicles to improve the targeted delivery of a range of therapeutic cargo. If you’d like to find out more about how Optimers could enable your next project, get in touch.