January 7, 2026

Tolerance vaccines, also called inverse vaccines, are designed to increase immune tolerance for an antigen. It is important to note that a tolerance (inverse) vaccine has not yet been approved by the FDA. However, several are in pre-clinical and clinical trials.

Traditional vaccines normally contain a moiety that resembles a disease-causing virus or bacterial cell, its toxin, or one of its surface proteins. The moiety is encountered by an APC (antigen presenting cell) and the APC presents the moiety to CD4 and CD8 T cells to provoke an immune response. Eventually, hopefully, memory T and B cells are created for a long-lasting immune response.

However, tolerance vaccines need to activate the tolerance components of the immune system. Tolerance (inverse) vaccines need to be cleverly designed to target cells of the immune system involved in tolerance, or locations in the body known to have a preference for tolerance, for example, the skin and the liver. The liver’s microenvironment favors immune tolerance and can result in the generation of regulatory T cells (Tregs). If successful in targeting particular cells to generate a tolerance response, tolerance vaccines have the potential to treat allergies and autoimmune diseases.

However, there are various therapeutic modalities that can be leveraged in the immune tolerance space. For example, administration of tolerogenic dendritic cells (tolDCs) or the use of peptides on the surface of nanoparticles. Science for Bankers’ Modalities MasterClass covers all therapeutic modalities, providing the background required to fully understand the possible therapeutic modalities that can be leveraged to increase immune tolerance.

December 3, 2025

RNA is well established in life sciences and biotech as both a therapeutic modality and a drug target. mRNA based vaccines and siRNA therapeutics have been successfully commercialized, while other types of RNA therapeutic products are still in pre-clinical and clinical development. However, long non-coding RNAs (lncRNAs) are still mysterious and their potential as a drug target remains unknown.

RNA is usually divided into coding RNA and non-coding RNA. Coding RNAs, like mRNA contain a 5’ cap, UTRs, a poly(A) tail, and a coding region for a protein. Non-coding RNA is a bit more elusive. Our current understanding is that non-coding RNA is involved in regulating gene expression and cell proliferation. For example, although miRNAs do not code for proteins, they bind to mRNA to alter its function.

Then there are long non-coding RNAs (lncRNAs), which are strands of RNA that are greater than 200 nucleotides. They also lack a protein coding region. Our current understanding is that lncRNA is involved in regulating gene expression and cell proliferation. Yet, their exact biological mechanisms are still being investigated. Researchers have documented distinct expression levels of lncRNA in patients with various diseases. However, how these expression levels translate as biomarkers, diagnostic agents, or even drug targets are not well understood. 

We currently know that lncRNA can be upregulated or down regulated in various diseases, but this does not mean that lncRNAs will serve as a potential drug target. We still do not know whether lncRNAs have specificity. If lncRNAs lack specificity for their natural biological target (cross-talk), then targeting lncRNAs could have adverse effects. As researchers continue to engage in basic research in the lncRNA space, their potential as a drug target may be revealed.   

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October 14, 2025

Antisense oligonucleotides (ASOs) are in the clinic for a variety of indications. When administrated, ASOs are susceptible to degradation before they even reach their intended target. To overcome this challenge, chemical modifications are made to the oligonucleotide; modifications such as phosphorothioate (PS-), 2′-O-methoxyethyl- (2′-MOE), or locked-nucleic-acid (LNA). These modifications enable the ASO to escape degradation or RNase H-mediated cleavage. 

Now, a new chemical modification strategy is being investigated: circular ASO (C-ASO). The hope is that C-ASO will overcome degradation susceptibility and have stability. While linear ASOs (L-ASOs) have chemical modification of the sugar-phosphate backbone or nucleotides, C-ASOs would only be circularized to avoid degradation and have stability in serum. The chemical modifications in L-ASOs can raise concerns regarding toxicity and triggering an immune response. C-ASOs could avoid these concerns.

If C-ASOs have increased stability and are able to alleviate toxicity and immunogenity concerns, could C-ASOs be best-in-class over their L-ASO counterparts? As data emerges from the clinic, this will need to be a therapeutic modality that is watched in the RNA therapy or ASO field.

Science for Bankers focuses on all things therapeutic modalities. Our Modalities Watch Blog keeps you informed on all the latest developments of therapeutic modalities.  Our Modalities MasterClass is a deep dive into therapeutic modalities. Enroll today in Science for Bankers’ Modalities MasterClass to master therapeutic modalities; a must for any biotech or pharma professional.

October 7, 2025

Cereblon E3 ligase modulators (CELMoDs) are a type of small molecule therapeutic modality in clinical development for the treatment of multiple myeloma. Specifically, CELMoDs are “molecular glues.” Although similar to PROTACs, molecular glues differ in their structure and mechanism of action.  

CELMoDs do not target and kill myeloma cells directly; their mechanism of action is more indirect. CELMoDs target cereblon, a protein in the human body that can form a protein complex with other proteins (DDB1, Cul4, and Rbx1) to create an E3 ligase (CRL4-cereblon). E3 ligases are involved in the Ubiquitin-Proteasome Pathway (UPP) which degrades proteins in the human body. E1, E2, and E3 proteins work in concert to tag a protein with ubiquitin. Once a protein is tagged with ubiquitin, it is marked for destruction by a proteasome.  

CELMoDs bind to cereblon to make it more likely to bind to certain proteins. The binding to cereblon modulates the function of the CRL4-cereblon E3 ligase, which in turns degrades certain transcription factors such as ikaros and aiolos. These transcription factors are over-expressed in multiple myeloma, and are needed for the cancer to proliferate. So, by degrading the ikaros and aiolos transcription factors, the cancer cells are unable to proliferate and multiple myeloma is treated.

CELMoDs are similar to IMiDs (immunomodulatory imide drugs), such as thalidomide, lenalidomide, and pomalidomide. IMiDs also bind cereblon to increase cereblon’s affinity for the ikaros and aiolos transcription factors. Looking forward, Iberdomide (CC-220) and mezigdomide (CC92480) are two CELMoDs to watch as they progress through the clinic.

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August 26, 2025

A new therapeutic modality, tiRNA (translation inhibition RNA), works by inhibiting translation of a protein. Most therapeutic modalities target a protein in the body to inhibit, suppress, block or degrade the protein. Certain therapeutic modalities target the mRNA that codes for the target protein, such as ASOs and siRNAs. ASOs can bind to mRNA and block the necessary proteins from translating the mRNA into the target protein. But tiRNA don’t just bind to mRNA to block out ribosomes and other RNA binding proteins. They are actually chimeras – having two different binding moieties joined by a linker.

tiRNAs have three parts: two binding moieties joined by a linker. One binding moiety binds to the 5’ untranslated region (5’UTR) of the target mRNA. The 5′ untranslated region is upstream from the initiation codon on a mRNA strand. This binding moiety is complementary to the 5’UTR. The second binding moiety binds to eIF4G (eukaryotic translation initiation factor 4 G), which is a protein involved in translation initiation. eIF4G is an interesting protein to target to prevent translation of mRNA into a protein because eIF4G is part of a complex that recruits the pre-initiation complex (PIC). The PIC is needed in order for translation to begin. By binding and immobilizing eIF4G, the PIC can’t be recruited, translation is inhibited, and the target protein is not produced.

The two binding moieties of tiRNAs have different composition of matter. The binding moiety that is complementary to the 5’UTR is an oligonucleotide and the moiety that binds to eIF4G can be a peptide, small molecule, small protein, or an aptamer.  A linker connects and spatially separates the two binding moieties. However, the tiRNA gets its specificity from the 5’UTR binding moiety. tiRNAs can target different mRNA strands based on the sequence of the oligonucleotide binding moiety of the tiRNA.

You can read more about tiRNAs here. Need to understand therapeutic modalities? Science for Bankers offers a MasterClass on therapeutic modalities which covers their composition of matter, mechanism of actions, how they are leveraged to treat diseases and disorders, and more.

Science for Bankers focuses on all things therapeutic modalities – tracking new innovations and discoveries, while offering a MasterClass on therapeutic modalities.

August 5, 2025

Designing a pro-drug is a well-known drug development strategy for small molecule modalities. A chemical moiety is bound to inactivate the small molecule drug. Once administered to a patient, the chemical moiety is cleaved, and the small molecule drug is activated. This same strategy is now being applied to large molecule modalities, such as antibodies, bispecifics, and fusion proteins.

Large molecule modalities such as antibodies, bispecifics, and fusion proteins have a variable region on the molecule that binds to its target. Drug development strategies are now being created to inactivate the large molecule drug, similar to how a pro-drug works. For example, a peptide is bound to the variable region of a large molecule drug to inactivate it by blocking it from binding to its target. Thus, creating a pro-body. However, for the large molecule drug to be activated, the peptide needs to be cleaved from the variable region, allowing the large molecule drug to bind to its target and assert is therapeutic effect.

Activating the pro-body, or cleaving the peptide from the variable region could be accomplished by a protease. A protease is a protein or enzyme in the body that can cleave or break down proteins. If the bonds between the peptide and the large molecule drug are recognized by a protease, then the peptide can be cleaved from the pro-body, activating the large molecule drug.

Ideally, a pro-body would be designed such that it is not activated until it has reached its therapeutic target. For example, if the target is a cell receptor that is expressed on healthy cells and on tumor cells, ideally, the pro-body would only be activated by proteases in the tumor microenvironment.

The promise of a pro-body drug development strategy is that it may lower on-target adverse effects, thus improving the overall therapeutic effectiveness of the large molecule drug.

Science for Bankers focuses on all things therapeutic modalities:  offering our Modalities MasterClass, our Modalities Watch Blog, and Modalities Training. Our Modalities MasterClass gets you up to speed on therapeutic modalities, and our Modalities Watch Blog keeps you current. A must for any ambitious life sciences professional.

July 31, 2025

Several molecular glues and degraders (or PROTACs) are currently in pre-clinical and clinical development. But a new small molecule therapeutic modality has emerged: molecular gates that are being developed by Gates Biosciences. 

Molecular glues and degraders are small molecule therapeutic modalities and are covered in Science for Bankers’ Modalities MasterClass. Molecular gates are also small molecules, but they have a completely different mechanism of action for targeting proteins. They work by binding and retaining a target protein within a cell so it can’t leave the cell. Retaining the target protein prevents it from reaching its desired location outside the cell and prevents it from performing its function.

Once made by a ribosome, a protein can remain in the cell (an intracellular protein) or it can leave the cell (an extracellular protein). If a protein needs to leave the cell in order to perform its function, it is secreted from the cell via a secretory pathway, or channel. A molecular gate molecule binds to the target protein and to the secretory channel, thus preventing the target protein from leaving the cell. Thus, molecular gates are able to target extracellular proteins by retaining them within cells.   

This clever approach expands the therapeutic possibilities for drugging extracellular proteins. Further, molecular gates have the potential to make certain undruggable proteins, druggable.

Science for Bankers centers on therapeutic modalities, offering our Modalities MasterClass, our Modalities Watch Blog, and Modalities Training. Our Modalities MasterClass gets you up to speed on therapeutic modalities and our Modalities Watch Blog keeps you current. A must for any ambitious life sciences professional.

July 22, 2025

Traditional antibodies are designed to bind to a target with a high affinity and then block some function of the target. For example, Opdivo is an antibody that binds to the PD-1 receptor to block its function. But antibody technology is evolving and moving beyond the traditional bind and block mechanisms of actions. Currently, scientists are investigating how to design antibodies with binding affinities that fluctuate based on the pH of the local environment.

Antibodies can bind at two different locations on the antibody. They can bind at the variable region and then can bind at the Fc region. Many antibodies in the clinic and that are approved have an extended half-life via recycling through binding with the neonatal Fc receptor (FcRn). It has been reported that the binding between the Fc region of the antibody and the FcRn is highly pH-dependent. Ideally, an antibody would bind to the FcRn in an acidic environment (like in an endosome) and dissociate from the FcRn at neutral pH (in the bloodstream). Thus, antibodies that are pH responsive are able to leverage the natural recycling function of the FcRn.

Besides endosomes, tumor microenvironments and areas of inflammation and ischemia are often acidic. Antibodies with binding affinities that fluctuate based on the local pH environment may be able to overcome some of the limitations of traditional antibodies. For example, where an antibody’s target is ubiquitously distributed throughout the body, a pH responsive antibody would have an enhanced binding affinity in the tumor microenvironment and areas of inflammation and ischemia. Fine tuning antibody binding to its target in these desired locations can lower off-target binding events, lower adverse effects, and improve therapeutic efficacy. pH responsive antibodies could facilitate precise targeting of cells in the treatment of major diseases and disorder.

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Antibodies are a popular and therapeutically effective modality. Traditional antibodies work by binding and blocking – binding to a target and then blocking its function. Humira works this way. It binds to TNF-alpha so it can’t bind to its receptor, thus blocking its activity. Other traditional antibodies may bind to a virus and block the virus from gaining entry into a cell, thus preventing the virus from replicating. Anti-PD-1 antibodies bind to the PD-1 receptor and block its activity.

Sweeping antibodies are a bit more sophisticated than the traditional binding and blocking antibodies. Sweeping antibodies are designed to bind to an antigen, then sweep it from the bloodstream. The variable region of the sweeping antibody binds to the antigen, but the Fc region binds to an FcRn receptor on a cell. The FcRn receptor promotes recycling of the antibody. Once bound and engulfed by the cell (FcRn mediated endocytosis), the antigen is degraded and the sweeping antibody is recycled and released by the cell. This sweeping antibody is then able to bind and degrade another antigen molecule.

Sweeping antibodies can target cytokines or other extracellular proteins that are implicated in certain diseases and disorders, especially autoimmune disorders. For a therapeutic strategy that requires eliminating or lowering an antigen’s concentration, a sweeping antibody might be the modality to leverage.

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July 8, 2025

LYTAC and PROTAC modalities set out to accomplish one thing: cause the degradation of a target protein. However, LYTAC and PROTAC modalities go about it in different ways.

PROTACs (PROteolysis TArgeting Chimeras), also called degraders, are small molecule modalities that link a target protein to an E3 ligase. Once linked, the E3 ligase transfers ubiquitin onto the target protein. The target protein tagged with ubiquitin becomes recognizable by a proteasome, which then degrades the target protein.

A PROTAC molecule can be leveraged in a therapeutic strategy to degrade a target protein that is linked to a disease. However, the location of the target protein is important. PROTACs can only target proteins that are inside cells (intracellular proteins). Arvinas has several PROTACs in the clinic, including Vepdegestrant (ARV-471). Vepdegestrant is being investigated in ER+ (estrogen receptor) breast cancer. Importantly, the targeted estrogen receptors are located inside cells.

But, what about target proteins located outside of cells? Those that are linked to neurological diseases?

LYTACs (LYsosome-TArgeting Chimeras) have the potential to target proteins found outside of cells. Because PROTACs leverage the ubiquitin-proteasome pathway, they are limited to targeting proteins that are found inside cells. LYTACs function by leveraging lysosomal proteolysis, mainly through receptor-mediated endocytosis. A LYTAC molecule binds to a target protein (located outside of a cell) and the LYTAC molecule also binds to a cell receptor that induces endocytosis. Once bound to the receptor, the LYTAC molecule and the target protein are engulfed by the cell and sent to a lysosome for degradation. Thus, LYTACs can target proteins found outside of cells for degradation.

LYTACs may be leveraged in diseases and disorders known to be associated with misfolded, mutated, or dysfunctional proteins found outside of cells. For example, prion diseases, Alzheimer’s, Parkinson’s, Huntington’s disease, and amyotrophic lateral sclerosis (ALS).

However, the development of LYTACs lags behind the advancement of PROTACs. A LYTAC molecule has not yet entered the clinic. Whether LYTACs gain attention and investment as a serious modality for treating diseases and disorders linked to dysfunctional extracellular proteins remains unknown.

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