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一种新一代 Fab 文库平台，可直接产生高亲和力、多样性和可开发性的类药抗体。

A next-generation Fab library platform directly yielding drug-like antibodies with high affinity, diversity, and developability.

机构信息

Specifica LLC, a Q2 Solutions Company, Santa Fe, NM, USA.

New Mexico Consortium, Los Alamos, NM, USA.

出版信息

MAbs. 2024 Jan-Dec;16(1):2394230. doi: 10.1080/19420862.2024.2394230. Epub 2024 Aug 27.

DOI:10.1080/19420862.2024.2394230
PMID:39192463
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11352698/
Abstract

We previously described an single-chain fragment (scFv) library platform originally designed to generate antibodies with excellent developability properties. The platform design was based on the use of clinical antibodies as scaffolds into which replicated natural complementarity-determining regions purged of sequence liabilities were inserted, and the use of phage and yeast display to carry out antibody selection. In addition to being developable, antibodies generated using our platform were extremely diverse, with most campaigns yielding sub-nanomolar binders. Here, we describe a platform advancement that incorporates Fab phage display followed by single-chain antibody-binding fragment Fab (scFab) yeast display. The scFab single-gene format provides balanced expression of light and heavy chains, with enhanced conversion to IgG, thereby combining the advantages of scFvs and Fabs. A meticulously engineered, quality-controlled Fab phage library was created using design principles similar to those used to create the scFv library. A diverse panel of binding scFabs, with high conversion efficiency to IgG, was isolated against two targets. This study highlights the compatibility of phage and yeast display with a Fab semi-synthetic library design, offering an efficient approach to generate drug-like antibodies directly, facilitating their conversion to potential therapeutic candidates.

摘要

我们之前描述了一个单链片段 (scFv) 文库平台，该平台最初是为了生成具有优异开发性能的抗体而设计的。该平台的设计基于使用临床抗体作为支架，将复制的、去除序列缺陷的天然互补决定区插入其中，并使用噬菌体和酵母展示来进行抗体选择。除了可开发性之外，使用我们的平台生成的抗体也非常多样化，大多数活动都产生了亚纳摩尔结合物。在这里，我们描述了一种平台改进，它结合了 Fab 噬菌体展示，然后是单链抗体结合片段 Fab（scFab）酵母展示。scFab 单基因格式提供了轻链和重链的平衡表达，并增强了转化为 IgG 的能力，从而结合了 scFv 和 Fab 的优势。使用类似于 scFv 文库设计中使用的设计原则，精心设计和质量控制的 Fab 噬菌体文库。针对两个目标分离了具有高 IgG 转化率的多样化 scFab 结合物。这项研究强调了噬菌体和酵母展示与 Fab 半合成文库设计的兼容性，提供了一种直接生成类药性抗体的有效方法，有助于将其转化为潜在的治疗候选物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a34/11352698/402844cd24fe/KMAB_A_2394230_F0010_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a34/11352698/c86036791f55/KMAB_A_2394230_F0001_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a34/11352698/210d2510ad96/KMAB_A_2394230_F0002_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a34/11352698/882c209079a1/KMAB_A_2394230_F0003_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a34/11352698/cdbeefe4aef9/KMAB_A_2394230_F0004_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a34/11352698/3ca796095fc1/KMAB_A_2394230_F0005_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a34/11352698/93cbb8cca0a8/KMAB_A_2394230_F0006_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a34/11352698/e3ba5d090b0b/KMAB_A_2394230_F0007_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a34/11352698/0d60a327da1a/KMAB_A_2394230_F0008_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a34/11352698/c707f84ff302/KMAB_A_2394230_F0009_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a34/11352698/402844cd24fe/KMAB_A_2394230_F0010_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a34/11352698/c86036791f55/KMAB_A_2394230_F0001_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a34/11352698/210d2510ad96/KMAB_A_2394230_F0002_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a34/11352698/882c209079a1/KMAB_A_2394230_F0003_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a34/11352698/cdbeefe4aef9/KMAB_A_2394230_F0004_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a34/11352698/3ca796095fc1/KMAB_A_2394230_F0005_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a34/11352698/93cbb8cca0a8/KMAB_A_2394230_F0006_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a34/11352698/e3ba5d090b0b/KMAB_A_2394230_F0007_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a34/11352698/0d60a327da1a/KMAB_A_2394230_F0008_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a34/11352698/c707f84ff302/KMAB_A_2394230_F0009_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a34/11352698/402844cd24fe/KMAB_A_2394230_F0010_B.jpg

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