We have developed a biophysical method to reduce the cost for antibody experiments in the fields of antibody-antigen, peptide-protein interaction, protein-protein interaction via data science.
Our method include:
-modification of antibody flexible chains,
-stepwise testing of each antibody to antigen,
-determination of key amino acid residues,
-range of changes in affinity.
-modification of antibody flexible chains,
-stepwise testing of each antibody to antigen,
-determination of key amino acid residues,
-range of changes in affinity.
AI
B2B. Cost -saving technologies for laboratory experiments
Fabs+Epitope
Input mutations in Fabs/Epitope
The goal of the AI ​​platform is to replace and reduce the number of intermediate in vitro experiments
1. The fraction of non-dissociated molecules after the reaction and concentration protein-ligand complex
2. Entropy Change. The case of one-dimensional normal distribution
3. Entropy Change. The case of multinormal normal distribution
4. Dissociation Constant: Kd, M/L
5. Enthalpy change: delta (P), J
6. The thermal dissociation
7. Potential energy of electrostatic interaction between all amino acid residues taken in pairs: Wp, J
8. Potential energy of the lower vibrational level: Wp1, J
9. Potential energy ofthe upper vibrational level: Wp2, J
10. Step-by-step verification of the PDB file structure.
2. Entropy Change. The case of one-dimensional normal distribution
3. Entropy Change. The case of multinormal normal distribution
4. Dissociation Constant: Kd, M/L
5. Enthalpy change: delta (P), J
6. The thermal dissociation
7. Potential energy of electrostatic interaction between all amino acid residues taken in pairs: Wp, J
8. Potential energy of the lower vibrational level: Wp1, J
9. Potential energy ofthe upper vibrational level: Wp2, J
10. Step-by-step verification of the PDB file structure.
Additional calculated parameters:
What do we have for obtaining information about the antibody-antigen affinity?
Each antibody-antigen complex has its own physical parameters that determine the interaction
Main calculated parameters:
Biophysics of the affinity of the antibody-antigen biocomplex.
High lifescience innovations
Our method will include modification of flexible chains of immunoglobults, stepwise testing of each antibody to antigen, determination of key amino acid residues, range of changes in affinity.
Antibody discovery and development has two main stages.
The first one is to discover antibodies that bind the target of interest. The second, is to optimize the antibody to make a better drug. This challenge is about the second step. The starting point is a functional antibody that modulate the desired target. We offer to build a computational platform that delivers the sequence of a modified antibody sequence. Modifications are required at multiple levels:
• Antibodies differ in their level of solubility, aggregation during purification, proper folding and more.
• Physiological properties: pharmacokinetic and pharmacodynamics.
The above list of properties required is not complete. The goal is not to optimize for a specific antibody property but rather to suggest a process to optimize to any property.
The first one is to discover antibodies that bind the target of interest. The second, is to optimize the antibody to make a better drug. This challenge is about the second step. The starting point is a functional antibody that modulate the desired target. We offer to build a computational platform that delivers the sequence of a modified antibody sequence. Modifications are required at multiple levels:
• Antibodies differ in their level of solubility, aggregation during purification, proper folding and more.
• Physiological properties: pharmacokinetic and pharmacodynamics.
The above list of properties required is not complete. The goal is not to optimize for a specific antibody property but rather to suggest a process to optimize to any property.
We passionately believe that medicine antibody development shouldn't be done alone - collaboration is essential for antibody-antigen development. That's why we are open for work with other innovators across the health landscape including academic scientists, patient organisations, governments, other bio-pharmaceutical companies and healthcare professionals.
Antibody affinity describes the intensity with which a single antibody molecule binds to its specific epitope in an antigen. This means that under a given concentration of antibody and antigen, a specific number of antigen–antibody complexes are formed. Consequently, antibody affinity is one of the major properties affecting the potency of therapeutic antibodies. Binders with higher affinities may allow lower doses or longer intervals of administration during therapy. Moreover, as antibodies require sophisticated production systems and therapeutic doses, and costs of goods of antibodies are comparably high, a high affinity may affect the commercial success of a therapeutic antibody. The process of in vivo affinity maturation is described as well as strategies for in vitro affinity maturation. Finally, the relation between affinity and efficacy and the determination of antibody affinity are reviewed.
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The correct determination of antibody affinity is crucial for antibody development as a wrong setup of the experiments may result in the further development of the wrong candidate antibody. This can result in low in vivo efficacy, especially when high-affinity antibodies are needed, for example, for neutralizing antibodies [1-2].
1. Barbas, C.F., Hu, D., Dunlop, N., Sawyer, L., Cababa, D., Hendry, R.M., Nara, P.L., and Burton, D.R. (1994) In vitro evolution of a neutralizing human antibody to human immunodeficiency virus type 1 to enhance affinity and broaden strain cross-reactivity. Proc. Natl. Acad. Sci., 91, 3809–3813.
2. Nelson, J.D., Brunel, F.M., Jensen, R., Crooks, E.T., Cardoso, R.M.F., Wang, M., Hessell, A., Wilson, I.A., Binley, J.M., Dawson, P.E. et al. (2007) An affinity-enhanced neutralizing antibody against the membrane-proximal external region of human immunodeficiency virus type 1 gp41 recognizes
2. Nelson, J.D., Brunel, F.M., Jensen, R., Crooks, E.T., Cardoso, R.M.F., Wang, M., Hessell, A., Wilson, I.A., Binley, J.M., Dawson, P.E. et al. (2007) An affinity-enhanced neutralizing antibody against the membrane-proximal external region of human immunodeficiency virus type 1 gp41 recognizes
How to measure and improve antibody-antigen affinity?
You do not need to perform preliminary expensive experiments to test different antibody modifications. Instead you can use the software developed by our team to determine the affinity of the antibody-antigen complex and affinity of its various modifications.
Procedure for finding suitable immunoglobulins
STEP ONE
1.Determination of three-dimensional complex of the target protein with antibody flexible chain, which is subject to further modification. This should be at least one file with the extension of the PDB obtained by the method of X-ray diffraction analysis or using molecular docking programs.
2.To control the received data, you can choose either of two options:
- you can use the additional structure of the PDB of antibody-antigen
-take advantage of previously available data on the mutations performed, alanine scanning of one of the participants of the antibody-antigen complex
3.Our experts check files, adapt them for computational manipulations using Soft Development and Data Science.
1.Determination of three-dimensional complex of the target protein with antibody flexible chain, which is subject to further modification. This should be at least one file with the extension of the PDB obtained by the method of X-ray diffraction analysis or using molecular docking programs.
2.To control the received data, you can choose either of two options:
- you can use the additional structure of the PDB of antibody-antigen
-take advantage of previously available data on the mutations performed, alanine scanning of one of the participants of the antibody-antigen complex
3.Our experts check files, adapt them for computational manipulations using Soft Development and Data Science.
STEP TWO
4. Our specialists perform the necessary calculations: obtain data, numerically calculate the results in the form of graphs and diagrams, determine
-key amino acid residues of antibody,
-interaction energies of antibody-antigen complex,
-changes in affinity and stability of antibody-antigen complex,
-change in entropy for each replacement of the amino acid residue in the flexible chain of immunoglobulin.
5. Performing a verification series of calculations in accordance with paragraph 2
4. Our specialists perform the necessary calculations: obtain data, numerically calculate the results in the form of graphs and diagrams, determine
-key amino acid residues of antibody,
-interaction energies of antibody-antigen complex,
-changes in affinity and stability of antibody-antigen complex,
-change in entropy for each replacement of the amino acid residue in the flexible chain of immunoglobulin.
5. Performing a verification series of calculations in accordance with paragraph 2
6. Analysis of the array of data obtained, selection of the most suitable replacements using soft and Data Science, report generation.
7.Sending the received data to the customer.
7.Sending the received data to the customer.
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In vitro antibody selection systems have been adopted to generate high-affinity binders. Error-prone polymerase ( error-prone polymerases are sometimes used in circumstances where the capacity to make errors has a selective advantage) chain reactions (PCRs) can be used to introduce amino acid exchanges randomly, either scattered over the whole Fv fragments or only in the CDRs [35]. The mutated DNA is subcloned into an appropriate expression vector for construction of an antibody library that is screened for high-affinity binders under modified panning conditions that allow enrichment of affinity-matured binders. Of course, the insertion of mutations in the Fv fragments with error-prone PCR cannot provide the whole theoretical diversity in these mutation libraries as this would exceed the possible library size. But the nucleic acid amino sequence diversity can be estimated using appropriate computer programs [36]. Nevertheless, screening of mutation libraries is widely used for the identification of beneficial amino acid exchanges not only in the CDRs but also in regions that are not directly involved in antigen binding.
Antigen Affinity - Affinity Measurement
The strength of antibody-antigen binding is enhanced by a fast association rate, which is proportional to the association rate constant (kon or ka), and by a slow dissociation rate, which is proportional to the dissociation rate constant (koff or kd). The value of affi nity is most frequently described by the equilibrium dissociation constant (KD). The KD, which is readily calculated by koff divided by kon, is the concentration of antibody-binding sites that will bind 50% of the antigen-binding sites when the concentration of antigen is much less than the KD. This simple defi nition of KD assumes that all antibody-binding sites are accessible to all antigen-binding sites and that no avid interactions occur. Avidity refl ects the strength of binding when multivalent binding results in a cooperative antigen– antibody interaction. An example of an interaction is when both antibodybinding sites simultaneously bind an antigen on a surface, or form cyclic or lattice immune complexes. In such cases, the avidity may be much stronger (by several orders of magnitude) than reflected by the 1 : 1 site binding KD. The values of KD, kon, and koff can be determined experimentally.
[The hidden world of drug interactions in anesthesia]
[The hidden world of drug interactions in anesthesia]
Development and testing of new antibodies using our biophysical software can significantly save money on laboratory research
