Axial — Observations #41. Get these analyses to your inbox —…
Tags: Venture Capital, Biotechnology, Investing, Healthcare, Medicine

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Observations #41

A set of ideas and observations from a week’s worth of work analyzing businesses and technologies.

Chemokines

Chemokines are the trafficking control system for the human immune system. They act as signposts to get different immune cells into certain organs. With over 50 different chemokines and 20 receptors (which are GPCRs), they are a class of cytokines that induce chemotaxis in nearby cells.

In 1987, the first chemokine cloned was CXCL8 (IL-8) for work around figuring out what factor(s) monocytes were secreting to attract neutrophils: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459227/ & https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4456961/

This sparked large-scale research efforts to clone chemokines and their receptors in the late-1980s and 1990s. This work led to the approval of drugs targeting CXCR4 and CCR5 to treat HIV and C5aR for ANCA-Associated Vasculitis (AAV). Despite the large number of new drug targets for inflammatory diseases generated from this work, dosing and target selection have been barriers for more successful chemokine-focused medicines.

As a result, there is a large opportunity to develop new medicines that target the chemoattractant system: (1) small molecules, as well as antibodies, to selectively target chemokines and their receptors and (2) engineered chemokines:

For autoimmunity, chemokines direct immune cells to self tissue

Viruses and microbes use chemokines to deceive the immune system

Vaccine responses can be improved with chemokines

Chemokines drive inflammatory diseases like AAV, diabetic nephropathy (DN), inflammatory bowel disease (IBD; targeting CCR9), and rheumatoid arthritis (RA; CCR1)

In cancer, angiogenesis is influenced by chemokines

Other diseases like Type 2 diabetes (T2D; CCR2) and chronic kidney disease (CKD) have also been found to be driven by inflammation where chemokines play a major role

The complex orchestration of chemokines and their various interactions with receptors make this space hard-to-drug. Not only does the target matter but the location and time of intervention are important as well. New opportunities with chemokines are centered around target selection for a disease, chemistry, and in vivo dosing:

Mapping in vivo interactions — figuring out systematically which chemokines bind specific receptors and at what doses and locations

Determining the biological response for each chemokine/receptor pair — different chemokines and receptors can have multiple functions depending on tissue, timing, and pairing. Excitedly, a small set of cells with activated chemokine receptors can lead to a large-scale immune response.

Immune cell subsets — which immune cell subsets respond to individual chemokines? For example in monocytes, CCR2 is a marker for an inflammatory class and CX3CR1 is one for the resident subset of monocytes.

Dosing — figuring out dosing in vivo; most work has been in vitro. Moreover, to generate a therapeutic effect, a large proportion of chemokine receptors need to be inhibited continuously, increasing the required critical dose. This requirement can lead to ADMET issues.

Target selection — determining whether a chemokine is redundant or not for a specific disease. For example, CCR7 is activated by both CCL21 and CCL19. Also, CCL5 activates 3 chemokine receptors: CCR1/3/5. Receptor internalization is different for each interaction. Chemokines have been seen as a hard-to-drug class of targets due to this potential redundancy.

Antibodies / engineered chemokines — develop antibodies for specific chemokines or receptors. Targeting chemokines, and using chemokines as a drug, requires knowing the concentration of the ligands in vivo. Pursuing receptors can become complex since they are GPCRs and have multiple transmembrane regions.

There is a large opportunity to bring new chemokine medicines to patients. The low-hanging fruit is to develop models and tools to predict which chemokine/receptor pair is involved in disease and develop a drug candidate to target the pair. In short, new methods are needed to figure out which part of the control system to block or add to?

The AgBiome Model

AgBiome is a large Agtech company with no managers. Rather, the company uses committees of employees to handle core functions like business development and financials. Eric Ward, Co-Founder and Co-CEO, took the lead to build this unique organizational structure at AgBiome — https://insights.som.yale.edu/insights/can-company-succeed-without-hierarchy

Their ideas started off with a management paper — https://cmr.berkeley.edu/search/articleDetail.aspx?article=4776 — to build a non-hierarchical structure at the startup. AgBiome might have the most unique operational structure in life sciences.

Jacob and Monod, and mRNA

With the first authorizations of two mRNA vaccines for COVID-19, mRNA is set up to transform medicine over the next few decades. Decades ago in 1961, Jacob and Monod first hypothesized what mRNA could be — https://www.gs.washington.edu/academics/courses/braun/55106/readings/jacob_and_monod.pdf

What is Life? cont.

In the final chapter (Is Life Based on the Laws of Physics?) of What is Life?, Schrödinger explores how life can emerge from the randomness of physics. The chapter focuses on two frameworks: (1) order-from-order (the traditional physics framework) and (2) order-from disorder (life):