Avidity and affinity definition relationship

Functional Avidity: A Measure to Predict the Efficacy of Effector T Cells?

avidity and affinity definition relationship

Affinity refers to the strength of any given bond between an antibody and its antigen. The strength of that overall connection is the avidity. Furthermore, the model predicted an inverse relationship between affinity and .. These are just simple examples of the interplay of affinity, avidity, and efficacy. By definition, T cells with high functional avidity respond in in vitro tests to very low The TCR affinity (Figure 1) refers to the physical strength of the This relationship may in parts explain why both K D and the time have.

Other studies have used a panel of altered peptide ligands in which the lack of correlation between TCR affinity and T-cell activation observed for some peptides could be a result of reduced stability of the peptide—major histocompatibility complexes pMHCs over the course of the activation assay ACT is often associated with autoimmunity in mouse 26 and human 627 melanoma due to the expression of tumor-associated antigens TAAs in normal tissues.

avidity and affinity definition relationship

One study of a diabetic mouse model using peptide vaccination indicated a correlation between ligand affinity and autoimmune response However, it has not previously been determined whether T cells expressing higher-affinity TCRs lead to more severe autoimmunity in ACT or the kinetic threshold that sets this fine balance.

Tetramer-based avidity measurements should not be confused with T-cell functional avidity 101131which refers to cellular responses in addition to binding.

Here we use the term functional activity to describe T-cell functional outcomes, such as cytokine release, cytotoxicity, and antitumor response. A modified epitope, gp—2M 33which enhances peptide stability ninefold while not altering pMHC structure 34is significantly more immunogenic 35 and has been widely used in clinical studies 36 Avidity, however, is the accumulated strength of multiple affinities summed up from multiple binding interactions and is commonly referred to as a functional affinity.

There are many factors that make effective tumor targeting with antibody-based molecules difficult. For example, one must overcome systemic clearance 39 capillary extravasation into the tumor, 10 and high interstitial pressure gradients 1112 to even gain exposure to the intended target antigen. Affinity and avidity of mAbs becomes a critical issue in tumor targeting when one begins to consider interactions with tumor-associated antigens.

Micropharmacological processes take place anywhere antigen recognition occurs. Not strictly limited to tumor cells, target antigen is commonly expressed on normal tissue, found in circulation, and shed into the tumor interstitial space. These nontarget pools of antigens can reduce treatment effectiveness, increase systemic clearance, and increase side-effects especially for radioimmunoconjugates by impairing mAb specificity for the tumor.

V delivery, it is commonly observed that mAbs have heterogenous, even perivascular, distribution within a tumor.

avidity and affinity definition relationship

Heterogeneous mAb distribution within a tumor can arise in part from heterogeneous antigen expression, heterogeneous vasculature, and necrosis. With the exception of antigen expression, these typical characteristics of tumors can perturb the distribution and penetration of any molecule entering the tumor, and, therefore, properties of the mAb should be inconsequential. However, in a seminal study, parameters thought to influence distribution and penetration were analyzed in a model algorithm for full mAb and mAb fragments.

By analyzing vasculature-wall penetration, molecular weight, valence, and antigen—mAb interactions, it was hypothesized that binding of the mAb to antigen can prevent its additional penetration. Simply stated, as affinity increases, penetration decreases. In subsequent models, the system was refined by exploring the shape of the hypothetical tumor, dose of mAb, vascular permeability, antigen density, nonspecific binding, and lymphatic outflow.

The critical factors predicted to affect the extent of the binding-site barrier are antigen density, mAb internalization and metabolism, and mAb binding affinity. In both studies, it was observed that the nonspecific mAb attained a low-level, ubiquitous distribution throughout the tumors, thereby demonstrating that mAbs can diffuse freely in the tumor, and no mechanical barrier inhibits penetration.

Large amounts of the specific mAb were retained on the perimeter of antigen-rich regions when given at a low dose.

Similarly, in multiple subcutaneous tumor xenograft models, it was observed that a low affinity mAb was more homogenously distributed throughout the tumor than a mAb with a fivefold higher affinity.

Journal of Immunology Research

Single-chain antibody fragments scFv are comprised of individual antigen-recognition sites from a mAb and have proven to be a very useful tool for investigating the role of affinity in tumor targeting and the binding-site barrier principle.

Through phage display and sequential mutagenesis, a panel of antihuman Her2 c-erbB-2 scFv were generated that target the same epitope with a wide range of binding affinities. After taking into account the high rate of scFv clearance by the kidneys, G98A also failed to achieve tumor levels higher than that in circulation after 24 hours in nephrectomized SCID mice bearing tumors.

Higher affinity scFv of the same panel C6. The monovalent immunoglobulin G IgG KD remained nearly the same as the initial scFv, but the functional affinity avidity increased to 5.

avidity and affinity definition relationship

Furthermore, IHC analysis revealed that C6. When used in in vitro antibody-dependent cellular cytotoxicity ADCC assays with donor-derived peripheral blood monocytes PBMCpotency proved to increase with monovalent affinity. Therefore, given that penetration decreases with affinity, and ADCC increases with affinity, future therapeutic designs will benefit from in vivo studies monitoring antitumor efficacy as a function of affinity and antigen density.

Internalization and Catabolism As discussed above, if a mAb is to diffuse into a tumor, there must be an appreciable concentration of free molecules. Binding antigen with slow dissociation rates high affinity can reduce the concentration of free mAb or scFv and limit penetration.

Affinity and Avidity in Antibody-Based Tumor Targeting

The concentration of free mAb can be reduced further if the antigen is internalized before the mAb dissociates. After internalization, the mAb can be degraded in the endosome and lysosome, but the antigen can be recycled or replaced by newly synthesized protein.

affinity vs avidity

In this case, the tumor, especially a large tumor with dense antigen expression, can become a significant sink for free mAb, limiting homogenous distribution. This effect is especially pronounced when the mAb off rate is slower than the rate of antigen internalization. Researchers that have investigated internalization with multiple mAbs or similar molecules are not in total agreement if properties of the targeting molecule have any effects on internalization or are is totally dependent on the antigen of interest.

This fraction was suggested to have only bound in a monovalent fashion.

Difference Between Affinity and Avidity

It was concluded that these mAbs were bound divalently, endocytosed, and degraded in the endosomal and lysosomal compartments. It does, however, seem reasonable to speculate from this study that, if the mAb dissociation rate is much slower than the rate of antigen internalization, mAb association with cellular antigen can be viewed as irreversible given that degradation will take place before equilibrium can be established.

In a recent study, Schmidt et al. Avidity is the measure of the overall strength of the interaction between antigenic epitopes with multivalence antibody.

avidity and affinity definition relationship

Occurence This occurs between individual epitope and individual binding site This occurs between multivalent antigens and antibodies. Value Affinity is the balance of attractive and repulsive forces.

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  • Affinity and Avidity in Antibody-Based Tumor Targeting

Avidity can considered as a value more than the sum of the individual affinities. It is similar to the enzyme substrate interaction. Specific antigen binds with a specific antibody. Affinity and avidity are two measures of this interaction. Affinity reflects the strength of one interaction between an epitope and an antigen binding site of the antibody. Avidity reflects the overall strength of the antigen antibody complex.