Antibody compounds binding classical target classes, as e.g. receptor tyrosine kinases or cytokines, are widely used as therapeutics. Innovative selection strategies have to be applied to broaden target space and bring antibodies against new target classes, as GPCRs, into clinical development. MOR210/TJ210 is a novel human antibody directed against C5aR1. C5aR1, the receptor of the complement factor C5a, is investigated as a potential new drug target in the field of immuno-oncology and autoimmune diseases.

LGR5 is highly expressed in colorectal tumors and marks cancer stem cells responsible for driving tumor growth. We generated LGR5-targeted antibody-drug conjugates (ADCs) and showed they could eliminate colorectal tumors in mouse models. However, a fraction of tumors eventually relapsed due to the dynamic plasticity of cancer cells. Our group is identifying new targets for ADC development and evaluating novel combination therapies to better target tumor cell plasticity and heterogeneity.

To enable the discovery of functional GPCR antibodies, Twist Biopharma grafted GPCR-binding motifs into a focused antibody library. By incorporating these motifs into the antibody heavy chain CDR3, we developed our first generation GPCR library. Another approach mined the patented GPCR antibody sequences using sequence information to guide the design of another synthetic library. The utility of both libraries demonstrated the ability to discover potent functional antibodies against multiple GPCR targets.

The expression of CXCR4 is low in non-diseased lung but upregulated in Idiopathic Pulmonary Fibrosis and other Interstitial lung diseases. CXCR4 is a central player in the progression of IPF and expressed in cell-types known to contribute to IPF/ILD. The single domain i-body AD-214 antagonises CXCR4 and is anti-fibrotic in several preclinical models of fibrosis and has recently been found to be safe in a first in human clinical trial.

As the pandemic continues, more transmissible SARS-CoV-2 variants that evade COVID-19 treatments have emerged. As part of its ongoing pandemic response, AbCellera discovered a highly potent monoclonal antibody, bebtelovimab (LY-CoV1404) from a convalescent COVID-19 patient sample that could present a long-term solution to the ongoing pandemic. Bebtelovimab targets a rarely-mutated epitope on the SARS-CoV-2 spike protein and potently neutralizes variants of concern, including the Delta variant.

Narcolepsy is a neurological disorder that impairs the brain's ability to control sleep-wake cycles. Agonists of the orexin receptor 2 (OX₂R) have shown promise as novel therapeutics that directly target the pathophysiology. Cryo-EM structures of OX₂R reveal that an extended carboxy-terminal segment of the endogenous peptide agonist OxB reaches into the core of OX₂R to stabilize an active conformation, while a recently discovered small-molecule agonist makes similar key interactions deep inside the orthosteric pocket. Comparison with antagonist-bound OX₂R suggests a molecular mechanism for receptor activation. The structures enable structure-based discovery of therapeutic orexin agonists for the treatment of narcolepsy.

Signaling through the CD19-CD81 co-receptor complex, in combination with the BCR, is a critical determinant of B cell development and activation. Upon binding to CD19, CD81 opens to expose a hydrophobic CD19-binding surface and reorganizes its transmembrane helices to occlude a cholesterol binding pocket present in the apoprotein. Our data reveal the structural basis for CD19-CD81 complex assembly, providing a foundation for rational design of therapies for B cell dysfunction.

We designed and generated six large (10 to11 each) human VH and VL antibody domain libraries displayed on phage. Selected binders were with good developability and highly effective against SARS-CoV-2 and related coronaviruses as Fc fusion proteins (Li W et al, Cell 2020; Sun Z et al mAbs 2020), including variants found in humans (Zhu X et al PLOS Biology 2021, Sun Z et al bioRxiv, 2021). Ongoing are efforts to improve them and generate new ones.

Soluble receptors can act as decoys to neutralize virus infection with reduced risk for the emergence of resistance. However, decoy receptors usually lack the specificity and affinity of monoclonal antibodies. Based on the receptors for human cytomegalovirus and SARS-CoV-2, decoys are engineered that resolve these challenges and are demonstrated to be safe and effective in vivo. The decoys broadly bind virus variants with tight affinity and limited potential for escape.

The recurrent zoonotic spillover of coronaviruses into humans underscores the need for broadly active countermeasures. We identified and engineered an antibody, ADG-2, that neutralizes SARS-CoV-2 variants of concern and representative SARS-like bat viruses with remarkable potency and protects against SARS and COVID-19 in animal models. ADG-2 is currently in clinical development for the treatment and prevention of SARS-CoV-2 and future emerging SARS-like CoVs.

The Specifica Generation3 Library Platform is based on highly developable clinical scaffolds, into which natural CDRs purged of sequence liabilities have been embedded. The platform uses phage and yeast display to directly yield highly diverse (100-1000 clusters differing by Levenshtein distance 30-40), high affinity (20% subnanomolar), developable (>80% lack biophysical liabilities), drug-like antibodies, which in a recent Covid campaign were as potent as antibodies from immune sources.

TRPA1 is a non-selective cation channel expressed in primary sensory neurons of the pain pathway. The physiological significance of TRPA1 has been highlighted by the discovery of genetic channelopathies where TRPA1 mutations result in severe pain disorders. Here, I present our data that describes the molecular mechanism of gain-of-function conferred by a novel TRPA1 channelopathy. Our results reveal a novel TRPA1 disease mechanism, paving the way for genetic tool building.

Spinal cord injury (SCI) causes severe disability. We developed an inhibitory antibody (MHC1) that inhibited connexin hemichannels, reduced secondary damage in two incomplete SCI mouse models. MHC1 after SCI significantly improved hind limb locomotion function by a single administration associated with decreased gliosis and lesion sizes, increased white and gray matter sparing, and improved neuronal survival. Targeting hemichannels with an antibody provides a new, innovative therapeutic approach in treating SCI.

We present cryo–EM structures of NPC1L1 in the apo form and complexed with ezetimibe to understand NPC1L1-mediated cholesterol transport and ezetimibe inhibition.. The apo structure represents an open state and the N-terminal domain interacts loosely with the rest of NPC1L1, leaving the central cavity accessible. The ezetimibe-bound form signifies a closed state in which the NTD rotates ~60°, creating a continuous tunnel enabling cholesterol movement into the plasma membrane. Ezetimibe blocks cholesterol transport by occluding the tunnel. These findings provide insight into the MOA of NPC1L1-mediated cholesterol transport and ezetimibe inhibition, paving the way for more effective therapeutic development.