Immunology and Biotherapies

Important issue!

Vaccines are a polarizing topic right now—easier to say it than ignore it.

But what isn’t polarizing is this: there are people and service members in remote, underserved, and conflict-affected parts of the world still vulnerable to some of the deadliest diseases on earth because of a lack of infrastructure. Diseases like Ebola and Marburg. And protection from them still requires deep freezers and trained clinicians to prepare and administer today’s tools.

Today, we announced new stability data on our intranasal vaccine candidate—a platform built on a well-established vector designed not just with the intention to protect, but to reach.

Grateful to everyone involved so far. Still more work to do, but this moonshot may just have legs. #AMR #Access

🐘 The first #mRNA vaccine for elephants!

Elephant endotheliotropic herpesvirus (EEHV) is the leading killer of baby Asian elephants. Professor Paul Ling at Baylor College of Medicine teamed up with Houston Zoo to develop a preventative vaccine using #mRNA technology. With support from Colossal Biosciences (the de-extinction/wooly mice company) they have evaluated the vaccine preclinically and have dosed their first elephant.

While #mRNA medicines for humans may get most of the headlines, development of applications for animal health are also accelerating.

Article: https://lnkd.in/gc_HPPB5

🚨#Immunogenicity can undermine any biologic, driven by anti-drug-antibodies (#ADA), from pre-clinical to post launch. This topic is so challenging due to the combination, intricacies and complexity of the molecules, human immunology, patient treatment journeys, assay standards and the vagaries of publishing. There is a ground truth but “for now we see through a glass, darkly”. Allowing for all that complexity, and briefly putting it to one side, are there any rules of thumbs we can see?

🫣What data shall we look at?

I decided to focus on the worst-case scenario and use the maximal ADA rates (the % of HV or patients across phase 1-4 reporting ADA post treatment) for #antibodies. With the help of a Deep Research tool I read the refs and extracted the published maximal ADA rates for these assets across all indications. So that’s:
• 54 #bisAb: 19 approved & 2 reg review, 13 phase 1-3, 20 terminated phase 1-3
• 129 #mAb: 75 approved | 16 phase 1-3 | 38 terminated phase 1-3

🎬 Findings:

1️⃣ mAb and bisAb clinical assets have a #similar spread of ADA profiles. The same observation was published this year in the IQ Survey Part 2 on immunogenicity for 46 mAb and 9 bisAb assets.
2️⃣ Mixtures of mAbs, co-formulated or co-administered, do not reduce immunogenicity risk.
3️⃣ Some targets do report higher ADA rates for almost all mAb and bisAb prosecuted in the clinic. This may primarily be MoA related but may also be due to the number of shots on goal the industry has tried.

🧐So what?

➡️ Each molecule is unique in its ADA risk profile. As we engineer our candidate drugs integrating an Immunogenicity Risk Assessment (#IRA) as part of our candidate target profile informs the risk and helps us select the candidate for IND.
🔂 The #translational #gap between the range of brilliant in vitro assays and patient response is still there.
↔️ Thank you to all the #patients, institutes and companies who put their data into the #public domain. As much as it’s in your remit please keep publishing the clinical ADA data. It’s part of enabling bedside to bench translation so we can do better next time💙

👍Over to #you🤔

❓What’s your view on de-risking preclinically and in vitro #assays?
🙋Who is curating this clinical data in a more robust way?

💬 it’s always good to chat the science through as “the truth is so obscure in these times… unless we love the truth, we can not know it” Blaise Pascal (1623-1662)

Effects of different B-cell-depleting strategies on the lymphatic tissue

- Advanced protein-based B cell depleters, such as glycoengineered CD20 monoclonal antibody obinutuzumab (OBI) and CD19/CD3 T cell engager blinatumomab (BLI), are promising new therapeutic instruments for treatment of autoimmune disease (AIDs).

- It has been speculated that such B cell-depleting modalities achieve better clearance of tissue B cells in patients.

- By performing sequential lymph node biopsies, this study shows that advanced protein-based B cell depleters, like OBI and BLI, reduce but do not consistently deplete B cells in the lymph nodes.

- These results stand in contrast to the consistent full depletion of B cells associated with the disruption of follicular lymph node architecture after CD19 chimeric antigen receptor T cell therapy.

- B cell depletion was associated with stable drug-free remission, whereas a reduction in B cell numbers without depletion required retreatment with immunomodulatory drugs.

-  Introducing lymph node biopsy as a clinical tool to assess B cell depletion could enhance treatment monitoring and play a pivotal role in tailoring therapeutic strategies.  Larger-scale studies are needed to confirm whether B cell depletion in secondary lymphoid organs directly correlates with clinical outcomes in patients with AID.

https://lnkd.in/eDdFr-_7

#autoimmunity #celltherapy #immunology #rheumatology

The FLUniversal consortium, supported by the EU’s Horizon Europe programme, is pioneering the development of an intranasal universal influenza vaccine. Our goal is to create a vaccine that offers broad protection against all flu strains, reducing the need for annual updates.
 
Key highlights of our approach include:
- Innovative Vaccine Design: Utilizing a live, replication-deficient influenza strain lacking the NS1 protein to stimulate a robust and lasting immune response.
- Intranasal Delivery: Administering the vaccine through the nose to induce strong local immunity, potentially preventing infection at its entry point.
- Comprehensive Testing: Employing controlled human infection models (CHIMs) to assess vaccine efficacy and identify immune correlates of protection.
- Preclinical Validation: Animal studies have demonstrated promising safety and immunogenicity results, laying a solid foundation for future clinical development.
 
This collaborative effort brings together leading experts from academia and industry, aiming to revolutionize influenza prevention.
 
Read the full article here: https://lnkd.in/dpYwW-PV

Vaccines are complex biological medicinal products developed with the aim to generate protective immunity against specific infectious diseases in

🚀 𝗖𝗲𝗹𝗹 𝗧𝗵𝗲𝗿𝗮𝗽𝘆 - 𝗧𝗵𝗲 (𝗥)𝗘𝘃𝗼𝗹𝘂𝘁𝗶𝗼𝗻
𝘍𝘳𝘰𝘮 𝘪𝘯𝘧𝘶𝘴𝘪𝘰𝘯𝘴 𝘵𝘰 𝘪𝘯𝘫𝘦𝘤𝘵𝘪𝘰𝘯𝘴?


Thrilled to have attended last week’s virtual "𝙄𝙣 𝙑𝙞𝙫𝙤 𝙀𝙣𝙜𝙞𝙣𝙚𝙚𝙧𝙞𝙣𝙜 𝙤𝙛 𝙄𝙢𝙢𝙪𝙣𝙚 𝘾𝙚𝙡𝙡𝙨 (𝙄𝙑𝙀𝙄𝘾)" workshop hosted by the 𝗡𝗖𝗜! 🚀

𝘐𝘯 𝘷𝘪𝘷𝘰 cell engineering is redefining the possibilities of immunotherapy—offering the potential for 𝗳𝗮𝘀𝘁𝗲𝗿, 𝗺𝗼𝗿𝗲 𝗮𝗰𝗰𝗲𝘀𝘀𝗶𝗯𝗹𝗲, 𝗮𝗻𝗱 𝗹𝗲𝘀𝘀 𝗿𝗲𝘀𝗼𝘂𝗿𝗰𝗲-𝗶𝗻𝘁𝗲𝗻𝘀𝗶𝘃𝗲 treatments compared to traditional 𝘦𝘹 𝘷𝘪𝘷𝘰 approaches.

𝗦𝗼𝗺𝗲 𝗸𝗲𝘆 𝗮𝗱𝘃𝗮𝗻𝘁𝗮𝗴𝗲𝘀 𝗶𝗻𝗰𝗹𝘂𝗱𝗲:
✅ No need for GMP manufacturing facilities
✅ Shorter and more scalable workflows
✅ Potential for outpatient or point-of-care delivery

⚠️ 𝗕𝘂𝘁 𝗰𝗵𝗮𝗹𝗹𝗲𝗻𝗴𝗲𝘀 𝗿𝗲𝗺𝗮𝗶𝗻:
- Reduced control over the engineering process
- Difficulties in targeting specific immune subsets
- Efficacy and safety still under active investigation


🔥 𝗬𝗲𝘁 𝘁𝗵𝗲 𝗺𝗼𝗺𝗲𝗻𝘁𝘂𝗺 𝗶𝘀 𝘂𝗻𝗱𝗲𝗻𝗶𝗮𝗯𝗹𝗲! 🔥


🌟 𝗦𝗼𝗺𝗲 𝗵𝗶𝗴𝗵𝗹𝗶𝗴𝗵𝘁𝘀:

- Carl June (University of Pennsylvania) laid the groundwork with a visionary keynote on 𝘦𝘹 𝘷𝘪𝘷𝘰 and 𝘪𝘯 𝘷𝘪𝘷𝘰 CAR-T.

- Matthias Stephan (WHI CCC Fred Hutchinson Cancer Research Center) showcased the power of local reprogramming via 𝘪𝘯 𝘷𝘪𝘷𝘰 engineering of macrophages to secrete BiTEs.

- Yevgeny Brudno (University of North Carolina at Chapel Hill Chapel Hill) introduced implantable sponges enabling same-day CAR T therapy.

- Cristiana Pires (Asgard Therapeutics) proposed turning tumors into antigen-presenting cells through 𝘪𝘯 𝘷𝘪𝘷𝘰 reprogramming.

- Daniel G. (Myeloid Therapeutics) shared early clinical data on 𝘪𝘯 𝘷𝘪𝘷𝘰 mRNA CAR myeloid engineering.

- Adrian Bot, M.D., Ph.D. (Capstan Therapeutics) presented Capstan’s LNP platform tackling both oncology and autoimmunity.

👏 Kudos to all the speakers and organizers for advancing this paradigm-shifting field.


⁉️ 𝙒𝙝𝙖𝙩 𝙖𝙧𝙚 𝙮𝙤𝙪𝙧 𝙩𝙝𝙤𝙪𝙜𝙝𝙩𝙨?

⁉️ 𝙒𝙝𝙖𝙩 𝙧𝙚𝙘𝙚𝙣𝙩 𝙞𝙣 𝙫𝙞𝙫𝙤 𝙙𝙖𝙩𝙖 𝙤𝙧 𝙥𝙡𝙖𝙩𝙛𝙤𝙧𝙢𝙨 𝙝𝙖𝙫𝙚 𝙘𝙖𝙪𝙜𝙝𝙩 𝙮𝙤𝙪𝙧 𝙖𝙩𝙩𝙚𝙣𝙩𝙞𝙤𝙣?



#Immunotherapy #InVivoEngineering #CellTherapy #CancerResearch #Biotech #CAR #GeneTherapy | 27 comments on LinkedIn

The search for potent malaria vaccine candidate has seen several twists and turns. Here, we provide a perspective on the current state of PfRH5-based malaria vaccine development, the progress, existing challenges, and future research directions. We discuss the clinical trials in endemic regions, immune correlates of protection, prospects of integrating PfRH5 into multi-antigen vaccine strategies and considerations on the onward development/deployment of PfRH5 vaccine from the laboratory to endemic communities.

Interesting paper
From ClinicalTrial.gov, the main different antigens targeted by CART-cells (Liquid and solid tumors) and how many times they have been (or are currently being) evaluated in clinical trials.
Not yet for IL-1RAP!

Significant regulatory shift in UK
that may impact 𝗖𝗔𝗥-𝗧 delivery:
At-patient manufacturing!
 
With summer holidays and other industry happening, this news may have passed you by (it did me!):

As of 23rd July 2025, the MHRA (the UK regulator) legally allows flexible, innovative manufacturing approaches such as Point-of-Care and decentralised/distributed modular manufacturing for ATMPs including CAR-Ts.
 
𝗪𝗵𝗮𝘁’𝘀 𝘁𝗵𝗲 𝗯𝗮𝗰𝗸𝗴𝗿𝗼𝘂𝗻𝗱 𝗳𝗼𝗿 𝘁𝗵𝗶𝘀:

🔹 MHRA innovation office has been receiving enquiries around this kind of manufacturing since 2014 – but no regulatory framework was in place to allow for PoC or modular manufacturing.
🔹 As technology advances – particularly ATMPs – new manufacturing modalities are required that can take place in hospitals, clinics and even the patients own home!

💭 𝗜𝗺𝗮𝗴𝗶𝗻𝗲 𝘁𝗵𝗮𝘁, 𝗵𝗮𝘃𝗶𝗻𝗴 𝗮𝗻 𝗮𝘂𝘁𝗼𝗹𝗼𝗴𝗼𝘂𝘀 𝗖𝗔𝗥-𝗧 𝗺𝗮𝗻𝘂𝗳𝗮𝗰𝘁𝘂𝗿𝗲𝗱 𝗮𝗻𝗱 𝗱𝗲𝗹𝗶𝘃𝗲𝗿𝗲𝗱 𝘄𝗶𝘁𝗵𝗶𝗻 𝘆𝗼𝘂𝗿 𝗼𝘄𝗻 𝗵𝗼𝗺𝗲.


𝗛𝗼𝘄 𝘄𝗶𝗹𝗹 𝗶𝘁 𝘄𝗼𝗿𝗸?

🔹  The technical solutions are still in development. Notably, Spain has made some great progress on establishing localised CAR-T production centres in Barcelona and Navarra.
🔹 A centralised “Hub” control site will be responsible for the decentralised “Spoke” sites; being responsible for documentation, quality, release and inspections.
🔹 A Decentralised Manufacturing Master File (DM MF) is required to be managed by the control site with annual reporting to MHRA
🔹 GMP and Pharmacovigilance requirements are maintained and must be have appropriate management plans prior to approval
 
𝗜𝗻 𝘀𝘂𝗺𝗺𝗮𝗿𝘆:

This legislation marks a significant regulatory shift, accommodating disruptive innovation in medicine manufacture and delivery. MHRA has adopted a flexible, guidance-led approach supported by stakeholder feedback, with a strong emphasis on collaboration and quality assurance.

Links to the MHRA webinar and the guidance document in the comments 👇

𝗧𝗵𝗶𝘀 𝗵𝗮𝘀 𝗯𝗲𝗲𝗻 𝗵𝗮𝗶𝗹𝗲𝗱 𝗮𝘀 𝗮 𝗳𝗶𝗿𝘀𝘁 𝗮𝗺𝗼𝗻𝗴 𝗿𝗲𝗴𝘂𝗹𝗮𝘁𝗼𝗿𝘀 – but do you think this puts the UK in a strong position for systems developers? 
💬 As always, let me know your thoughts in the comments below. | 26 comments on LinkedIn

📣 We have today announced the launch of the world’s first library of immune-boosting adjuvants that can be ‘taken off the shelf’ and used to enhance new vaccines being developed against epidemic and pandemic threats.

The $2.5 million project—funded and led by CEPI—will act as a matchmaking service, helping vaccine developers select the best vaccine-adjuvant combinations to make their vaccines more potent and effective. The UK’s Medicines and Healthcare products Regulatory Agency will host the repository of 25 adjuvants shared by leading research institutes and medical companies around the world.
 
Vaccine-enhancing adjuvants have played a powerful role in transforming our response to deadly diseases over the past century. The ingredients are added to the majority of vaccines to enhance the immune response, creating stronger and longer lasting protection against infections than the vaccine alone.

In the case of an outbreak of a new Disease X, the adjuvant library could help quickly identify the top-performing vaccine-adjuvant pairings to contain the spread of the virus before it reaches pandemic proportions. 
 
🔗 Discover more in the link below.

Ever wondered about monoclonal antibody applications? The image contains every FDA-approved monoclonal antibody arranged by therapeutic areas.

Bi- and tri-specific antibodies are hot topics, but classical monoclonals (mAbs) are the workhorses of modern biotherapeutics.

In 1975, Georges Köhler and César Milstein, working in Cambridge, unlocked a new era of medicine with the development of the hybridoma technique.

That was the first method for mass-producing mAbs.

The first therapeutic mAb (Orthoclone OKT3) was approved in 1986, but there are now >100 FDA-approved mAbs.

➟ Oncology and haematology remain dominant applications of mAbs.

➟ Neurology and dermatology are growing fast with CGRP blockers and IL-23/IL-17 inhibitors.

➟ Interestingly, nearly 40 % of approvals are outside of cancer. I thought it would have been less.

Do you think bi-specifics will catch up?

---

* Data source: The Antibody Society.

** Some antibodies are approved for multiple therapeutic areas, and commercial rights may vary across jurisdictions or under specific licensing agreements.

#Immunotherapy | "Right Time, Right Place" | Lymph Node-targeted temporally programmed #STING nanoadjuvant delivery unlocks synergistic chemotherapy-induced anti-#Tumor #Immunity | Breaking at Science Magazine Advances |

Stimulator of interferon genes (STING) agonists have attracted notable attention for their potent immune activation capabilities. However, their clinical application is hindered by systemic toxicity and delivery inefficiencies.

Here*, researchers addressed these challenges by developing a lymph node–targeted STING agonist nanoadjuvant (Mn/MSA-2@Lipo) combined with a temporally optimized delivery strategy. Mn/MSA-2@Lipo uses manganese ions to amplify STING pathway activation while achieving efficient lymph node accumulation and antigen presentation.

They first induced immunogenic cell death (ICD) through chemotherapy to release tumor antigens, followed by the administration of the nanoadjuvant at an optimized time interval, the approach effectively synchronizes dendritic cell (DC) antigen uptake and maturation. This combination therapy notably enhanced antitumor immunity in melanoma and breast cancer models, achieving complete tumor regression and inducing long-lasting immune memory, all while demonstrating an excellent safety profile.

These findings highlight the critical importance of delivery timing optimization, offering a promising strategy for the clinical translation of STING agonists and the design of advanced immunotherapies.

*https://lnkd.in/epVJs-GE

Celentyx Ltd #immunooncology #drugdiscovery www.celentyx.com

Professor Nicholas Barnes PhD, FBPhS Omar Qureshi Catherine Brady

SUMMARY FIGURE | (A) Schematic of temporally programmed STING nanoadjuvant delivery unlocks synergistic chemotherapy-induced antitumor immunity | (B). Schematic representation of the temporally programmed delivery strategy. The top panel illustrates the optimal sequence of chemotherapy and nanoadjuvant delivery. Administering Mn/MSA-2@Lipo 48 hours after Doxil allows DCs to capture tumor antigens prior to maturation, enabling efficient cross-presentation to CD8+ T cells in the tdLNs. This strategy enhances CD8+ T cell activation, subsequent tumor cell destruction, and long-term immune memory. The bottom panel depicts premature adjuvant administration, leading to early DC maturation, reduced phagocytic capacity, and diminished antitumor immune responses |

IL-7–expanded CD8+ T cells demonstrate increased accumulation within orthotopic glioblastoma models despite endogenous T cell sequestration in bone marrow. Though peripherally administered, activated autologous T cells have been shown to cross the BBB under physiologic conditions (28), their...

𝐂𝐀𝐑 𝐓 𝐓𝐡𝐞𝐫𝐚𝐩𝐲 𝐢𝐧 𝐍𝐨𝐧-𝐎𝐧𝐜𝐨𝐥𝐨𝐠𝐲 👇

CAR T cell therapy has transformed cancer treatment, but its potential extends far beyond oncology.

The figure below illustrates diverse CAR T cell targets in non-oncological diseases:

- Autoimmune diseases,
- Infections,
- Fibrosis,
- Haemophilia,
- Aging.

Exciting see the next-gen CARs tackle areas beyond oncology. Dual-targeting CARs (e.g., CD19-BCMA for lupus) are proving especially effective in tackling treatment-resistant diseases.

#oncology #immunology #celltherapy #CGTweekly

The response to vaccination depends on many factors and is based on the 4 Ws: Who, When, What, and Where.

In this article, the authors, focusing on the last W (Where), sought to identify the determinants associated with a better response to booster vaccination when administered at the same site as the initial vaccination.

They were able to show that in mice Bmems in dLNs reside in a subcapsular niche rich in CD169+ macrophages (SSMs) that interact closely with these cells, promoting their re-entry into germinative centers (GCs) after booster vaccination. Bmems in ndLNs (non-draining LNs) are more dispersed, migrate deeper into the follicles, and preferentially differentiate into plasma cells rather than GC cells.

The study in the mouse model was supplemented by a study in humans comparing, as has been done in the past, ipsilateral versus contralateral booster vaccination with a COVID-19 mRNA vaccine, demonstrating the superiority of ipsilateral vaccination.

In vivo CAR engineering for immunotherapy

In this Review, the authors discuss current strategies for in vivo CAR engineering of T cells and other immune cells and explore future directions and potential applications for the advancement of in vivo CAR engineering technologies.

- Chimeric antigen receptor (CAR)-engineered immune cell therapy represents an important advance in cancer treatments. However, the complex ex vivo cell manufacturing process and stringent patient selection criteria curtail its widespread use.

- In vivo CAR engineering is emerging as a promising off-the-shelf therapy, providing advantages such as streamlined production, elimination of patient-specific manufacturing, reduced costs and simplified logistics.

- Among the various approaches to in vivo CAR engineering, LNP–mRNA-based CARs have a strong chance of reaching the clinic first, leveraging the manufacturing and regulatory advancements established during the COVID-19 pandemic.

- Preclinical proof-of-concept studies in cancer and cardiac injury models have demonstrated functional equivalence between therapeutic cells that were engineered in vivo and those produced via conventional ex vivo methods.

- Before taking in vivo CAR engineering to the clinic, it is essential to conduct a comparative analysis across the various vector technologies to identify those that provide an optimal balance among efficacy, immunogenicity and safety.

- Patient selection for in vivo CAR engineering would be likely to prioritize individuals with relatively intact immune systems, as endogenous T cells must respond to the in vivo gene delivery, expand and persist for therapeutic efficacy. This could exclude heavily pretreated patients with profound lymphopenia or those with a highly immunosuppressive TME.

https://lnkd.in/ePhBCVsS

#celltherapy #CART #immunotherapy